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WO2024140319A1 - Pyrimidine compound, and preparation method therefor and medical use thereof - Google Patents

Pyrimidine compound, and preparation method therefor and medical use thereof Download PDF

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Publication number
WO2024140319A1
WO2024140319A1 PCT/CN2023/139755 CN2023139755W WO2024140319A1 WO 2024140319 A1 WO2024140319 A1 WO 2024140319A1 CN 2023139755 W CN2023139755 W CN 2023139755W WO 2024140319 A1 WO2024140319 A1 WO 2024140319A1
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Prior art keywords
alkyl
cycloalkyl
aryl
heteroaryl
alkynyl
Prior art date
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PCT/CN2023/139755
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French (fr)
Chinese (zh)
Inventor
王铁林
宋海峰
肖璐
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Jiangsu Yahong Meditech Co Ltd
Asieris Pharmaceuticals Shanghai Co Ltd
Original Assignee
Jiangsu Yahong Meditech Co Ltd
Asieris Pharmaceuticals Shanghai Co Ltd
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Priority to CN202380083590.6A priority Critical patent/CN120303260A/en
Publication of WO2024140319A1 publication Critical patent/WO2024140319A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a pyrimidine compound used as an ATR inhibitor, a preparation method thereof, a pharmaceutical composition containing the pyrimidine compound, and use thereof in treating ATR kinase-mediated diseases, such as cancer.
  • DDR DNA damage response
  • Ataxia telangiectasia mutated gene Rad3-related kinase belongs to the serine-threonine kinase of the phosphatidylinositol 3-kinase (PIKK) family.
  • PIKK phosphatidylinositol 3-kinase
  • ATR kinase When ATR kinase is activated in the presence of DNA damage, it can regulate cellular biological processes through a variety of signals, including cell cycle arrest, inhibition of replication origins, promotion of deoxynucleotide synthesis, initiation of replication forks, and repair of DNA double-strand breaks, thereby avoiding cell apoptosis.
  • the DNA damage repair system in most tumor cells is abnormal, and usually lacks certain repair pathways (such as mutations in p53 or ATM), making them more dependent on ATR for survival.
  • inhibiting ATR kinase alone will not have a significant effect. Therefore, inhibiting ATR may have a more significant effect on the treatment of cancer, while having less interference with normal cells, making ATR a promising target for cancer treatment.
  • ATR inhibitors can be used alone or as sensitizers for DNA-damaging chemotherapy or radiotherapy, other DDR inhibitors, and immune checkpoint inhibitors.
  • Widely used combination therapy drugs include antimetabolites (such as gemcitabine), DNA cross-linking agents (such as cisplatin, carboplatin), alkylating agents (such as temozolomide), topoisomerase inhibitors (such as camptothecin, topotecan, irinotecan), other DDR inhibitors (PARP inhibitors), etc.
  • Combination therapy inhibits ATR under elevated levels of replication stress, thereby inhibiting the ability of cancer cells to repair damaged DNA, greatly enhancing the therapeutic effect of cancer.
  • the present invention has designed and synthesized a new class of pyrimidine compounds, which can be used as ATR kinase inhibitors for treating diseases such as cancers that are linked to ATR kinase.
  • the object of the present invention is to provide a compound represented by general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from hydrogen, alkyl, alkenyl, alkynyl, and the alkyl, alkenyl, alkynyl is optionally substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkoxy, halohydroxyalkyl, alkenyl, alkynyl;
  • Ring A is selected from aryl, heteroaryl, cycloalkyl or heterocyclyl, and the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with one or more Q groups;
  • Q is selected from hydrogen, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl, heteroaryl, -( CH2 ) qNRaRb , - ( CH2 ) qRc , -( CH2 )qORc, -( CH2 ) qC ( O)Rc, -(CH2)qC(O)ORc, -(CH2)qOC ( O ) Rc , - ( CH2 ) qC ( O ) NRaRb , wherein the alkyl , alkoxy , alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl , and heteroaryl groups are optionally further selected from halogen , amino, oxo , thio , nitro , cyan
  • R2 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, wherein the alkyl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl;
  • R3 is selected from alkyl, haloalkyl or cycloalkyl
  • R a and R b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q NR d R e , -(CH 2 ) q R f , -(CH 2 ) q OR
  • R c is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d and Re together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
  • Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • n 0, 1, 2 or 3;
  • p 0, 1, or 2;
  • q is an integer from 0 to 6.
  • L is selected from a bond, an alkylene group, an alkenylene group, an alkynylene group, -C(O)-, -S(O)-, -S(O) 2 -, -C(O)NH-, -S(O)NH-, -S(O) 2 NH-, -C(O)O-; preferably selected from a bond, an alkylene group, -C(O)-;
  • Ring A is selected from aryl, heteroaryl, preferably C 6-10 aryl or 5-10 membered heteroaryl; the aryl, heteroaryl is optionally substituted by one or more Q groups;
  • Q is selected from hydrogen, halogen, amino, hydroxyl, thiol, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl, heteroaryl , -( CH2 ) qNRaRb , - ( CH2 )qRc, -( CH2 )qORc , -( CH2 ) qC (O) Rc , -( CH2 ) qC (O) ORc , -( CH2 ) qOC (O) Rc , -( CH2 ) qC ( O ) NRaRb , - ( CH2 ) qS ( O ) pRc , -( CH2 ) qS (O ) pNRaRb , -NRcC ( O) NRaRb , -NRcC ( O) NRaRb
  • R a and R b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q NR d R e , -(CH 2 ) q R f , -(CH 2 ) q OR
  • Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl , mercapto, alkyl , alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl , -( CH2 ) qNRdRe , -( CH2 ) qRf , -( CH2 ) qORf , - ( CH2 ) qC (O) Rf , -(CH2) qC (O) ORf , -( CH2 ) qOC (O) Rf , -(CH2)qC(O)NRdRe, -C(O)NRf(CH2)qNRdRe , - ( CH2 ) qS ( O ) pRf , - ( CH2 )
  • R c is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d and Re are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R d and Re together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;
  • Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • q is an integer from 0 to 6.
  • ring A is selected from the following groups:
  • Ring A is optionally further substituted by Q, wherein Q is as defined in the general formula (I).
  • R2 is hydrogen or C1-6 alkyl
  • L is selected from -CH 2 -, -C(O)-;
  • Ring A is selected from phenyl or 5- to 6-membered heteroaryl, preferably phenyl; Ring A is optionally further substituted by -(CH 2 ) q NR a R b ;
  • q is 1 or 2, preferably 1;
  • Ra and Rb are each independently selected from hydrogen or C1-6 alkyl.
  • the compound represented by the general formula (I) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof is a compound represented by the general formula (II) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,
  • Q1 is -NR a R b ;
  • q is an integer from 1 to 6, preferably an integer from 1 to 4, more preferably 1 or 2;
  • Rf is hydrogen or C 1-6 alkyl
  • p is 1 or 2, preferably 2;
  • R 5 is selected from hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -(CH 2 ) q NR d R e , -NR d C(O) R f , -S(O) p NR d R e ;
  • R6 is selected from hydrogen, halogen, amino and C1-6 alkyl
  • Rf is hydrogen or C 1-6 alkyl
  • p 2;
  • R d is selected from hydrogen, C 1-6 alkyl
  • R e is selected from hydrogen, C 1-6 alkyl
  • p 2;
  • Y is selected from CR 5 R 6 ;
  • X 1 and X 2 are each independently selected from CH or N;
  • Y 1 is selected from N or CR 6 ;
  • R6 is selected from hydrogen, halogen, amino and C1-6 alkyl
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, 5 to 6 membered heteroaryl, -(CH 2 ) q NR d R e , wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, 5 to 6 membered heteroaryl is optionally further substituted with one or more substituents selected from halogen, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 haloalkyl, 3 to 6 membered heterocyclyl;
  • R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl
  • R7 and R8 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group, preferably a 6 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylamino, C3-6 cycloalkyl, 3-8 membered heterocyclic group, wherein the C3-6 cycloalkyl, 3-8 membered heterocyclic group is optionally further substituted with one or more groups selected from halogen, C1-6 alkyl, C1-6 haloalkyl;
  • R d and Re are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl is optionally further substituted with one or more substituents selected from halogen;
  • R d and Re together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group is optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;
  • R 10 is selected from C 1-6 alkyl, C 1-6 haloalkyl
  • q is an integer from 1 to 4, preferably 1 or 2;
  • n 0, 1 or 2;
  • R 2 , R 3 , R 4 and m are as defined in the general formula (I); Q 2 is as defined in the general formula (II).
  • Y 1 is selected from CR 6 ;
  • R6 is selected from hydrogen, halogen, amino and C1-6 alkyl.
  • R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl (e.g. oxetanyl, azetidinyl, pyranyl, furanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl), phenyl, 5-6 membered heteroaryl (e.g.
  • R 8 is selected from hydrogen, C 1-6 alkyl
  • R d is selected from C 1-6 alkyl
  • R e is selected from C 1-6 alkyl
  • R d and Re together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl);
  • oxetanyl piperidinyl, piperazinyl, morpholinyl
  • C 3-6 cycloalkyl, 3-8 membered heterocyclic group is optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl.
  • R 11 and R 12 together with the carbon atom to which they are attached form a 3-12-membered heterocyclic group, preferably a 3-6-membered heterocyclic group; the heterocyclic group is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8-membered heterocyclic group, aryl, heteroaryl;
  • R d and Re are each independently selected from hydrogen and C 1-6 alkyl
  • Rf is selected from C 1-6 alkyl
  • q is an integer from 0 to 4, preferably an integer from 0 to 2;
  • R 2 , R 3 , R 4 and m are as defined in the general formula (I); Q 2 and n are as defined in the general formula (II).
  • Q 1 is selected from NR a R b ;
  • R a is selected from hydrogen and C 1-6 alkyl
  • R b is selected from C 1-6 alkyl, preferably C 1-4 alkyl, wherein the alkyl is optionally further substituted by a substituent selected from -NR d R e , -NR d C(O)R f , -C(O)NR d R e ;
  • the compound represented by the general formula (I) or the general formula (II) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof is the compound represented by the general formula (IV) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein,
  • Each R 13a is independently selected from hydrogen, halogen, C 1-6 alkyl; s is 0, 1, 2, 3 or 4, preferably 0, 1 or 2;
  • Ring M is selected from 5-6 membered heterocyclic groups, preferably 6 membered heterocyclic groups;
  • R 13 and R 14 together with the carbon atom to which they are attached form a 3-12 membered heterocyclic group, preferably a 3-6 membered heterocyclic group; the heterocyclic group is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl;
  • q is an integer from 0 to 6;
  • Typical compounds of the present invention include, but are not limited to:
  • the present invention also relates to the compounds represented by the general formula (I) according to the present invention or their stereoisomers, A method for preparing a variant isomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:
  • the base is preferably an organic base or an inorganic base
  • the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate
  • the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (diisopropylethylamine);
  • the condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluor
  • the reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
  • a solvent preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
  • the present invention also relates to a method for preparing the compound represented by the general formula (II) according to the present invention or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:
  • the condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluor
  • the reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
  • a solvent preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
  • the present invention also relates to a method for preparing the compound represented by the general formula (III) according to the present invention or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:
  • the base is preferably an organic base or an inorganic base
  • the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate
  • the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (diisopropylethylamine);
  • the condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluor
  • the reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
  • a solvent preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
  • R 2 , R 3 , R 4 , X 1 to X 4 , Y, Q 2 , m and n are as defined in the general formula (III).
  • the condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluor
  • the reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
  • a solvent preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
  • R 2 , R 3 , R 4 , R 7 , R 8 , X 1 , X 2 , Y 1 , Q 2 , m and n are as defined in the general formula (IIIA).
  • the present invention also relates to a method for preparing the compound represented by general formula (IIIC) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:
  • the base is preferably an organic base or an inorganic base
  • the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate
  • the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (diisopropylethylamine);
  • the base is preferably an organic base or an inorganic base
  • the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate
  • the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (diisopropylethylamine);
  • the reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
  • a solvent preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;
  • R 2 , R 3 , R 4 , R 13a , R 13b , X 1 , X 2 , Y 3 to Y 6 , Q 2 , m, n and s are as defined in the general formula (IV).
  • the present invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the present invention or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
  • the present invention further relates to the use of the compound according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of ATR kinase inhibitors.
  • the present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts or to pharmaceutical compositions comprising them, for use as ATR kinase inhibitors.
  • the present invention also relates to a method for inhibiting ATR kinase, which comprises administering to a subject in need thereof an effective amount of a compound according to the present invention or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
  • the compound of the present invention can be reacted with an acid to form a pharmaceutically acceptable acid addition salt.
  • the acid includes inorganic acids and organic acids, and particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tris(2-hydroxy-1-nitropropenesulfonic acid) and 1-(2-hydroxy-1-nitropropenesulfonic acid). Fluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, colorants and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain active ingredients and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing.
  • Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.
  • Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oil suspension may contain a thickener such as beeswax, hard paraffin or cetyl alcohol.
  • the above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation.
  • These compositions may be preserved by adding an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.
  • the pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion.
  • the oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate.
  • Emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants.
  • Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain a demulcent, a preservative, a coloring agent, and an antioxidant.
  • the pharmaceutical composition of the present invention can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be prepared according to known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents.
  • the sterile injection preparation can also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol.
  • sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be used to prepare injections.
  • the present invention can contain the general formula compound and its pharmaceutically acceptable salt, hydrate or solvate as active ingredient, mixed with pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form.
  • the derivative of the present invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions, etc.
  • the compound of the present invention can be used as the only active ingredient, or it can be used in combination with other therapeutic drugs. Combined therapy is achieved by administering each therapeutic component simultaneously, separately or successively.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds described in the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include pro
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, an alkyl group containing 1 to 4 carbon atoms or an alkyl group containing 1 to 3 carbon atoms.
  • alkylene groups include, but are not limited to, methylene (—CH 2 —), 1,1-ethylene (—CH(CH 3 )—), 1,2-ethylene (—CH 2 CH 2 —), 1,1-propylene (—CH(CH 2 CH 3 )—), 1,2-propylene (—CH 2 CH(CH 3 )—), 1,3-propylene (—CH 2 CH 2 CH 2 —), and 1,4-butylene (—CH 2 CH 2 CH 2 CH 2 —), and the like.
  • the alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • ring atoms preferably, it contains 4 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 7 to 12 ring atoms, of which 1 to 4 are heteroatoms.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.
  • hydroxy refers to -OH.
  • acyl refers to a compound of the group -C(O)R, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • a “pharmaceutical composition” is a composition containing one or more of the compounds described herein or a physiologically/pharmaceutically acceptable A mixture of a salt or prodrug with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions.
  • protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, T. W. Greene and G. M. Wuts's “Protective Groups in Organic Preparations” (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts are given in units of 10 -6 (ppm). NMR measurements are performed using a WNMR-I-400MHz nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • the known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Inokai, Anaiji Chemical, Shanghai Bid, Nanjing Yaoshi and other companies.
  • Reaction solvent organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc.
  • the solution refers to an aqueous solution.
  • reaction progress in the examples was monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction were: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: acetone, and the volume ratio of the solvents was adjusted according to the polarity of the compounds.
  • TLC thin layer chromatography
  • the eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system.
  • A dichloromethane and methanol system
  • B petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.
  • Compound A1-2 (15 g, 98.5 mmol, 1.0 eq.) was dissolved in anhydrous ACN (150 mL), and CuBr (21.5 g, 150 mmol, 1.5 eq.) was added.
  • Tert-butyl nitrite (16 g, 150 mmol, 1.5 eq.) was added dropwise at 70°C with stirring, and stirred at 70°C for 4 hours. 300 mL of water was added to the reaction mixture, and 300 mL of ethyl acetate was added.
  • Step 2 Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxylic acid (A2)
  • Step 2 Preparation of methyl 1-(3-fluoro-5-nitropyridin-4-yl)piperidine-4-carboxylate (A3-3)
  • Step 3 Preparation of methyl 1-(3-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylate (A3-4)
  • Step 4 Preparation of 1-(3-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid (A3)
  • Step 1 Preparation of methyl 3-amino-6-(4-(methylsulfonyl)phenyl)pyrazine-2-carboxylate (1-3)
  • 3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (1-1) (500 mg, 2.16 mmol, 1.00 eq), (4-(methylsulfonyl)phenyl)boric acid (1-2) (476 mg, 2.38 mmol, 1.1 eq), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (354 mg, 0.43 mmol, 0.2 eq), sodium carbonate (459 mg, 4.3 mmol, 2.00 eq) were dissolved in dioxane (10 mL) and water (1 mL), and reacted at 100 ° C for 1.5 hours under nitrogen atmosphere.
  • Step 3 Preparation of 3-amino-6-(4-(methylsulfonyl)phenyl)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrazole-2-carboxamide (1)
  • Step 1 Preparation of tert-butyl (4-((3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamido)methyl)benzyl)(methyl)carbamate (2-2)
  • reaction mixture was quenched with water (30 ml), extracted with ethyl acetate, washed with saturated NaHCO 3 , washed with saturated brine, and concentrated under reduced pressure to obtain a colorless transparent liquid compound 2-2 (800 mg, yield 92%, purity 95%).
  • HATU 100 mg, 0.26 mmol, 1.2 eq.
  • DMF 2.0 mL
  • compound 54-4 66 mg, 0.26 mmol, 1.2 eq.
  • compound A2 73 mg, 0.22 mmol, 1.0 eq.
  • DIPEA 0.12 mL, 0.66 mmol, 3.0 eq.
  • Step 1 Preparation of (3-(piperidin-1-yl)azetidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (100-3)
  • Step 2 Preparation of (4-(3-amino-5-fluoropyridin-4-yl)phenyl)(3-(piperidin-1-yl)azetidin-1-yl)methanone (100-4)
  • HATU 34 mg, 0.089 mmol, 1.2 eq.
  • DMF 1 mL
  • compound 101-4 20 mg, 0.074 mmol, 1.0 eq.
  • compound A2 28.6 mg, 0.089 mmol, 1.2 eq.
  • DIPEA 28 mg, 0.22 mmol, 3.0 eq.
  • Raney nickel (188 mg, 1.89 mmol, 20.0 eq) was added to a solution of compound 56 (90 mg, 0.16 mmol, 1.0 eq) in aqueous ammonia-methanol (6 ml), and the mixture was reacted at room temperature for 48 h.
  • Test Example 1 ATR in vitro enzyme activity inhibition experiment
  • Test Example 2 Experimental study on the inhibitory activity of the compounds of the present invention on 22RV1 (human prostate cancer cells) and MDA-MB-436 (breast cancer cells) cells proliferation
  • 22RV1 cells purchased from Nanjing Kebai Biotechnology Co., Ltd.
  • MDA-MB-436 cells purchased from Nanjing Kebai Biotechnology Co., Ltd.
  • 22RV1 cells purchased from Nanjing Kebai Biotechnology Co., Ltd.
  • MDA-MB-436 cells purchased from Nanjing Kebai Biotechnology Co., Ltd.
  • the cell plate was equilibrated to room temperature, and then 50uL of CellTiter-Glo solution was added to each well.
  • the compounds of the present invention have good cell proliferation inhibitory activity against 22RV1 (human prostate cancer cells) and MDA-MB-436 (breast cancer cells).

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Abstract

The present invention relates to a pyrimidine compound, and a preparation method therefor and the medical use thereof. Specifically, the present invention relates to a compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing same, and the use thereof as an ATR kinase inhibitor in the treatment of ATR kinase-mediated diseases. The definition of each group in the general formula (I) is the same as that in the description.

Description

一种嘧啶类化合物及其制备方法和医药用途A pyrimidine compound and its preparation method and medical use 技术领域Technical Field

本发明属于药物化学领域，具体涉及一种用作ATR抑制剂的嘧啶类化合物、其制备方法、含有其的药物组合物及其在治疗ATR激酶介导的疾病中的用途，例如癌症的治疗。The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a pyrimidine compound used as an ATR inhibitor, a preparation method thereof, a pharmaceutical composition containing the pyrimidine compound, and use thereof in treating ATR kinase-mediated diseases, such as cancer.

背景技术Background technique

DNA在外部环境或者细胞内部的各种因素作用下可不断产生损伤。如果未修复或异常修复，这些病变可能导致细胞死亡，甚至引起基因有害突变。为了保证细胞基因组的稳定性和完整性，细胞已经形成了一个复杂的信号通路网络，统称为DNA损伤反应(DNA damage response,DDR)。DDR负责协调DNA损伤的早期检测，并向细胞周期检查点和DNA修复途径发送信号，暂停细胞周期以启动修复，或在损伤过于严重时启动细胞死亡。研究发现，健康细胞存在多种DDR机制，且这些修复机制可以在DNA修复过程中彼此补偿。而许多癌细胞中多种DNA修复通路存在缺陷，因此对未受损的DNA修复通路表现出更大的依赖性。DNA can be continuously damaged by various factors in the external environment or inside the cell. If not repaired or repaired abnormally, these lesions may lead to cell death or even harmful genetic mutations. In order to ensure the stability and integrity of the cell genome, cells have formed a complex network of signaling pathways, collectively known as the DNA damage response (DDR). DDR is responsible for coordinating the early detection of DNA damage and sending signals to cell cycle checkpoints and DNA repair pathways to pause the cell cycle to initiate repair or initiate cell death when the damage is too severe. Studies have found that healthy cells have multiple DDR mechanisms, and these repair mechanisms can compensate for each other during the DNA repair process. However, many cancer cells have defects in multiple DNA repair pathways, so they show greater dependence on intact DNA repair pathways.

共济失调毛细血管扩张突变基因Rad3相关激酶(ATR)属于磷脂酰肌醇3-激酶(PIKK)家族中的丝氨酸-苏氨酸激酶，在DNA损伤时ATR激酶被激活后，可通过多种信号调控细胞生物过程，包括细胞周期阻滞、抑制复制起点、促进脱氧核苷酸合成、启动复制叉以及修复DNA双链断裂，从而避免细胞凋亡。大部分肿瘤细胞中的DNA损伤修复系统异常，通常缺失一定的修复通路(如p53或ATM的突变)，使得其更加依赖ATR来存活。而在正常细胞中，由于其健全完整的修复通路，单独抑制ATR激酶不会产生较大影响。因此，抑制ATR可能对癌症的治疗具有更显著的效果，而对正常细胞干扰较少，使ATR成为有希望的癌症治疗靶点。Ataxia telangiectasia mutated gene Rad3-related kinase (ATR) belongs to the serine-threonine kinase of the phosphatidylinositol 3-kinase (PIKK) family. When ATR kinase is activated in the presence of DNA damage, it can regulate cellular biological processes through a variety of signals, including cell cycle arrest, inhibition of replication origins, promotion of deoxynucleotide synthesis, initiation of replication forks, and repair of DNA double-strand breaks, thereby avoiding cell apoptosis. The DNA damage repair system in most tumor cells is abnormal, and usually lacks certain repair pathways (such as mutations in p53 or ATM), making them more dependent on ATR for survival. In normal cells, however, due to their sound and complete repair pathways, inhibiting ATR kinase alone will not have a significant effect. Therefore, inhibiting ATR may have a more significant effect on the treatment of cancer, while having less interference with normal cells, making ATR a promising target for cancer treatment.

ATR抑制剂可以单独使用，也可以作为DNA损伤化疗或放疗、其他DDR抑制剂和免疫检查点抑制剂的增敏剂。广泛应用的联合治疗药物包括抗代谢药(如吉西他滨)、DNA交联剂(如顺铂、卡铂)、烷化剂(如替莫唑胺)、拓扑异构酶抑制剂(如喜树碱、拓扑替康、伊立替康)、其他DDR抑制剂(PARP抑制剂)等。联合治疗在复制应激水平升高的情况下抑制ATR，从而抑制癌细胞修复受损DNA的能力，使得癌症的治疗效果大大增强。ATR inhibitors can be used alone or as sensitizers for DNA-damaging chemotherapy or radiotherapy, other DDR inhibitors, and immune checkpoint inhibitors. Widely used combination therapy drugs include antimetabolites (such as gemcitabine), DNA cross-linking agents (such as cisplatin, carboplatin), alkylating agents (such as temozolomide), topoisomerase inhibitors (such as camptothecin, topotecan, irinotecan), other DDR inhibitors (PARP inhibitors), etc. Combination therapy inhibits ATR under elevated levels of replication stress, thereby inhibiting the ability of cancer cells to repair damaged DNA, greatly enhancing the therapeutic effect of cancer.

虽然已有多种ATR激酶抑制剂公开(例如M6620、WO2011154737、WO2016020320、WO2010071837、WO2014089379、WO 2020087170、WO 2020049017等)，但目前为止仍没有ATR抑制剂上市，因此发现更加有效且安全的ATR抑制剂仍十分必要。
Although a variety of ATR kinase inhibitors have been disclosed (e.g., M6620, WO2011154737, WO2016020320, WO2010071837, WO2014089379, WO 2020087170, WO 2020049017, etc.), no ATR inhibitors have been marketed so far, so it is still necessary to find more effective and safe ATR inhibitors.

发明内容Summary of the invention

本发明经过潜心研究，设计合成了一类新的嘧啶类化合物，该化合物可以用作ATR激酶抑制剂，用于治疗ATR激酶接到的疾病如癌症。After intensive research, the present invention has designed and synthesized a new class of pyrimidine compounds, which can be used as ATR kinase inhibitors for treating diseases such as cancers that are linked to ATR kinase.

因此，本发明的目的是提供一种通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
Therefore, the object of the present invention is to provide a compound represented by general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

其中：in:

R1选自氢、烷基、烯基、炔基，所述烷基、烯基、炔基任选被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷氧基、卤羟烷基、烯基、炔基的一个或多个取代基所取代；R 1 is selected from hydrogen, alkyl, alkenyl, alkynyl, and the alkyl, alkenyl, alkynyl is optionally substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkoxy, halohydroxyalkyl, alkenyl, alkynyl;

或者，R1为 Alternatively, R1 is

其中：in:

L选自键、亚烷基、亚烯基、亚炔基、-C(O)-、-S(O)-、-S(O)2-、-C(O)NH-、-S(O)NH-、-S(O)2NH-、-C(O)O-；L is selected from a bond, alkylene, alkenylene, alkynylene, -C(O)-, -S(O)-, -S(O) 2- , -C (O)NH-, -S(O)NH-, -S(O)2NH-, -C(O)O-;

环A选自芳基、杂芳基、环烷基或杂环基，所述芳基、杂芳基、环烷基或杂环基任选被一个或多个Q基团取代；Ring A is selected from aryl, heteroaryl, cycloalkyl or heterocyclyl, and the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with one or more Q groups;

Q选自氢、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、 -(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRc(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRc(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc的一个或多个取代基所取代；Q is selected from hydrogen, halogen, amino, hydroxyl, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl, heteroaryl, -( CH2 ) qNRaRb , - ( CH2 ) qRc , -( CH2 )qORc, -( CH2 ) qC ( O)Rc, -(CH2)qC(O)ORc, -(CH2)qOC ( O ) Rc , - ( CH2 ) qC ( O ) NRaRb , wherein the alkyl , alkoxy , alkenyl, alkynyl, cycloalkyl , heterocyclyl, aryl , and heteroaryl groups are optionally further selected from halogen , amino, oxo , thio , nitro , cyano , hydroxy , thiol , alkyl , haloalkyl, alkoxy , haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl, -(CH2)qNRaRb, - ( CH2)qRc, -( CH2 )qORc, - ( CH2) qNRaS (O) pRc ; wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl , and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, thiol, alkyl , haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl, -( CH2 )qNRaRb , -(CH2) qRc , -( CH2 ) qORc , -(CH - ( CH2 ) qC (O) ORc , -( CH2 ) qOC (O) Rc , -( CH2 ) qC (O)NRaRb, -C(O) NRc ( CH2 ) qNRaRb , -(CH2)qS(O)pRc, -(CH2)qS ( O ) pNRaRb , -NRc ( O ) NRaRb , - ( CH2 ) qNRaC (O)Rc, -(CH2)qNRaC ( O ) ORc or - ( CH2 ) qNRaS (O ) pRc ;

R2选自氢、卤素、烷基、烯基、炔基，所述烷基、烯基、炔基任选被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基的一个或多个取代基所取代； R2 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, wherein the alkyl, alkenyl, alkynyl is optionally substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl;

或者，R1和R2与其相连的氮原子一起形成杂环基或杂芳基，所述杂环基或杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb的一个或多个取代基所取代；Alternatively, R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic group or a heteroaryl group, which is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group , aryl, heteroaryl , -( CH2 ) qNRaRb ;

R3选自烷基、卤代烷基或环烷基； R3 is selected from alkyl, haloalkyl or cycloalkyl;

每个R4各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤烷氧基、卤羟烷基、烯基、炔基、烷基磺酰基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；each R 4 is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkoxy, halohydroxyalkyl, alkenyl, alkynyl, alkylsulfonyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ra和Rb各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；R a and R b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q NR d R e , -(CH 2 ) q R f , -(CH 2 ) q OR f , -(CH 2 ) q C (O)R f , -(CH 2 ) q C(O)OR f , - ( CH 2 ) q OC(O)R f , -(CH 2 ) q -C(O)NR d R e , -C(O)NR f (CH 2 ) q NR d R e , -(CH 2 ) q S(O) p R f , -(CH 2 ) q S(O) p NR d R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O)R f , -(CH 2 ) q NR d C(O)OR f or -(CH 2 ) q NR d S(O) p R f ;

或者，Ra和Rb与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、 -C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, -( CH2 ) qNRdRe , -(CH2) qRf , -(CH2) qORf , -( CH2 ) qC (O) Rf , -( CH2 ) qC (O) ORf , -( CH2 )qOC(O) Rf , -( CH2 ) qC (O)NRdRe, -(CH2)qRf, -(CH2)qORf, -( CH2 ) qOC (O) Rf , -( CH2 ) qC ( O) NRdRe , -( CH2 ) q -C(O) NRf ( CH2 ) qNRdRe , -(CH2)qS(O)pRf, -(CH2)qS ( O ) pNRdRe , -NRdC ( O ) NRdRe , - (CH2)qNRdC(O)Rf, -(CH2 ) qNRdC ( O ) ORf , or -( CH2 ) qNRdS (O ) pRf ; the alkyl, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

Rc选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R c is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Rd和Re各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、氨酰基、烷基氨酰基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R d and Re are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

或者，Rd和Re与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、二烷基氨基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个取代基所取代，所述环烷基和杂环基任选进一步被选自卤素、烷基、卤代烷基的一个或多个基团所取代；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;

Rf选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

m为0、1、2或3；m is 0, 1, 2 or 3;

p为0、1或2；p is 0, 1, or 2;

q为0至6的整数。q is an integer from 0 to 6.

在一个实施方案中，所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，In one embodiment, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

R1为 R1 is

其中： in:

L选自键、亚烷基、亚烯基、亚炔基、-C(O)-、-S(O)-、-S(O)2-、-C(O)NH-、-S(O)NH-、-S(O)2NH-、-C(O)O-；优选自键、亚烷基、-C(O)-；L is selected from a bond, an alkylene group, an alkenylene group, an alkynylene group, -C(O)-, -S(O)-, -S(O) 2 -, -C(O)NH-, -S(O)NH-, -S(O) 2 NH-, -C(O)O-; preferably selected from a bond, an alkylene group, -C(O)-;

环A选自芳基、杂芳基，优选C6-10芳基或5-10元杂芳基；所述芳基、杂芳基任选被一个或多个Q基团取代；Ring A is selected from aryl, heteroaryl, preferably C 6-10 aryl or 5-10 membered heteroaryl; the aryl, heteroaryl is optionally substituted by one or more Q groups;

Q选自氢、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc的一个或多个取代基所取代；Q is selected from hydrogen, halogen, amino, hydroxyl, thiol, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl, heteroaryl , -( CH2 ) qNRaRb , - ( CH2 )qRc, -( CH2 )qORc , -( CH2 ) qC (O) Rc , -( CH2 ) qC (O) ORc , -( CH2 ) qOC (O) Rc , -( CH2 ) qC ( O ) NRaRb , - ( CH2 ) qS ( O ) pRc , -( CH2 ) qS (O ) pNRaRb , -NRcC ( O) NRaRb , - ( CH2 ) qNRaC ( O) Rc , -( CH2 ) qNRa wherein the alkyl , alkoxy , alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy , haloalkoxy, hydroxyalkyl, alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) qNRaRb , -( CH2 ) qRc , -( CH2 )qORc, -( CH2 ) qC ( O ) Rc , -( CH2 ) qC (O) ORc , - ( CH2 ) qOC (O) Rc , -( CH2 ) qC (O) NRaRb , -C(O) NRc ( CH2 ) q NR a R b , -(CH 2 ) q S(O) p R c , -(CH 2 ) q S(O) p NR a R b , -NR c C(O)NR a R b , -(CH 2 ) q NR a C(O)R c , -(CH 2 ) q NR a C(O)OR c or -(CH 2 ) q NR a S(O) p R c ;

Ra和Rb各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；R a and R b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q NR d R e , -(CH 2 ) q R f , -(CH 2 ) q OR f , -(CH 2 ) q C (O)R f , -(CH 2 ) q C(O)OR f , - ( CH 2 ) q OC(O)R f , -(CH 2 ) q -C(O)NR d R e , -C(O)NR f (CH 2 ) q NR d R e , -(CH 2 ) q S(O) p R f , -(CH 2 ) q S(O) p NR d R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O)R f , -(CH 2 ) q NR d C(O)OR f or -(CH 2 ) q NR d S(O) p R f ;

或者，Ra和Rb与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl , mercapto, alkyl , alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl , -( CH2 ) qNRdRe , -( CH2 ) qRf , -( CH2 ) qORf , - ( CH2 ) qC (O) Rf , -(CH2) qC (O) ORf , -( CH2 ) qOC (O) Rf , -(CH2)qC(O)NRdRe, -C(O)NRf(CH2)qNRdRe , - ( CH2 ) qS ( O ) pRf , - ( CH2 ) qS (O) pNRd R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O) R f , -(CH 2 ) q NR d C(O) OR f or -(CH 2 ) q NR d S(O) p R f substituted with one or more substituents; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

Rc选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、 炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R c is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, Alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxy, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Rd和Re各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、氨酰基、烷基氨酰基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R d and Re are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

或者，Rd和Re与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、二烷基氨基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个取代基所取代，所述环烷基和杂环基任选进一步被选自卤素、烷基、卤代烷基的一个或多个基团所取代；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;

Rf选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p为0、1或2；p is 0, 1, or 2;

q为0至6的整数。q is an integer from 0 to 6.

在一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中环A选自以下基团：
优选为环A任选进一步被Q取代，Q如通式(I)所定义。In a specific embodiment, according to the compound represented by the general formula (I) of the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A is selected from the following groups:
Preferably Ring A is optionally further substituted by Q, wherein Q is as defined in the general formula (I).

在一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中： In a preferred embodiment, the compound represented by the general formula (I) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

R1为 R1 is

R2为氢或C1-6烷基； R2 is hydrogen or C1-6 alkyl;

L选自-CH2-、-C(O)-；L is selected from -CH 2 -, -C(O)-;

环A选自苯基或5至6元杂芳基，优选苯基；环A任选进一步被-(CH2)qNRaRb；Ring A is selected from phenyl or 5- to 6-membered heteroaryl, preferably phenyl; Ring A is optionally further substituted by -(CH 2 ) q NR a R b ;

q为1或2，优选1；q is 1 or 2, preferably 1;

Ra和Rb各自独立地选自氢或C1-6烷基。 Ra and Rb are each independently selected from hydrogen or C1-6 alkyl.

在另一个实施方案中，所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
In another embodiment, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

其中：in:

L选自键、亚烷基、-C(O)-；优选为键；L is selected from a bond, an alkylene group, -C(O)-; preferably a bond;

X1、X2、X3、X4各自独立地选自CH或N；X 1 , X 2 , X 3 , and X 4 are each independently selected from CH or N;

Q1选自氢、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc的一个或多个取代基所取代； Q is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl , -( CH2 ) qNRaRb , -( CH2 ) qRc , -( CH2 )qORc , -( CH2 ) qC (O) Rc , -( CH2 ) qC (O) ORc , -( CH2 ) qOC (O) Rc , - ( CH2 ) qC ( O ) NRaRb , - ( CH2 ) qS (O) pRc , -( CH2 ) qS ( O)pNRaRb , -NRcC(O)NRaRb, - ( CH2 ) qNRaC ( O) Rc , -( CH2 ) q NR a C(O)OR c or -(CH 2 ) q NR a S(O) p R c ; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q NR a R b , -(CH 2 ) q R c , -(CH 2 ) q OR c , -(CH 2 ) q C(O)R c , -(CH 2 ) q C(O ) OR c , -(CH 2 ) q OC(O)R c , -(CH 2 ) q C(O)NR a R b , -C(O) NR c (CH 2 ) qNRaRb , - (CH2)qS(O)pRc, -(CH2)qS ( O ) pNRaRb , -NRcC ( O ) NRaRb , - ( CH2 ) qNRaC (O) Rc , - ( CH2 ) qNRaC ( O) ORc or -( CH2 ) qNRaS (O ) pRc ;

每个Q2各自独立地选自氢、卤素、烷基、卤代烷基、-(CH2)qC(O)NRaRb，所 述烷基任选进一步被NRaRb取代；Each Q 2 is independently selected from hydrogen, halogen, alkyl, haloalkyl, -(CH 2 ) q C(O)NR a R b , The alkyl group is optionally further substituted with NR a R b ;

Ra和Rb各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；R a and R b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q NR d R e , -(CH 2 ) q R f , -(CH 2 ) q OR f , -(CH 2 ) q C (O)R f , -(CH 2 ) q C(O)OR f , - ( CH 2 ) q OC(O)R f , -(CH 2 ) q -C(O)NR d R e , -C(O)NR f (CH 2 ) q NR d R e , -(CH 2 ) q S(O) p R f , -(CH 2 ) q S(O) p NR d R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O)R f , -(CH 2 ) q NR d C(O)OR f or -(CH 2 ) q NR d S(O) p R f ;

或者，Ra和Rb与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl , mercapto, alkyl , alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl , -( CH2 ) qNRdRe , -( CH2 ) qRf , -( CH2 ) qORf , - ( CH2 ) qC (O) Rf , -(CH2) qC (O) ORf , -( CH2 ) qOC (O) Rf , -(CH2)qC(O)NRdRe, -C(O)NRf(CH2)qNRdRe , - ( CH2 ) qS ( O ) pRf , - ( CH2 ) qS (O) pNRd R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O) R f , -(CH 2 ) q NR d C(O) OR f or -(CH 2 ) q NR d S(O) p R f substituted with one or more substituents; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

Rc选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R c is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Rd和Re各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、氨酰基、烷基氨酰基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R d and Re are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

或者，Rd和Re与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、二烷基氨基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个取代基所取代，所述环烷基和杂环基任选进一步被选自卤素、烷基、卤代烷基的一个或多个基团所取代； Alternatively, R d and Re together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;

Rf选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

n为0、1或2；n is 0, 1 or 2;

R2、R3、R4、m、p、q如通式(I)所定义。R 2 , R 3 , R 4 , m, p and q are as defined in the general formula (I).

在另一个实施方案中，所述的通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，In another embodiment, the compound represented by the general formula (II) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

Q1为-NRaRb； Q1 is -NR a R b ;

Ra和Rb各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRd(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；R a and R b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q NR d R e , -(CH 2 ) q R f , -(CH 2 ) q OR f , -(CH 2 ) q C (O)R f , -(CH 2 ) q C(O)OR f , - ( CH 2 ) q OC(O)R f , -(CH 2 ) q -C(O)NR d R e , -C(O)NR d (CH 2 ) q NR d R e , -(CH 2 ) q S(O) p R f , -(CH 2 ) q S(O) p NR d R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O)R f , -(CH 2 ) q NR d C(O)OR f or -(CH 2 ) q NR d S(O) p R f ;

或者，Ra和Rb与其相连的氮原子一起形成4-10元杂环基，优选4-6元杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、烯基、炔基、C3-6环烷基、3-8元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group, preferably a 4-6 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, C3-6 cycloalkyl, 3-8 membered heterocyclic group, C6-10 aryl, 5-6 membered heteroaryl , -( CH2 ) qNRdRe , -( CH2 ) qRf , -( CH2 ) qORf , -( CH2 ) qC (O) Rf , -( CH2 ) qC (O) ORf , -( CH2 ) qOC (O) Rf , -( CH2 ) qC (O) NRdRe , -C (O) NRf ( CH2 ) qNRdRe , -(CH2) wherein the alkyl , alkenyl , alkynyl , cycloalkyl , heterocyclyl , aryl and heteroaryl groups are optionally substituted by one or more substituents selected from halogen, amino , oxo , thio , nitro , cyano , hydroxyl , thiol, alkyl, haloalkyl , alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups ;

Rd和Re各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、氨酰基、烷基氨酰基、烯基、炔基、C3-6环烷基、3至6元杂环基、C6-10芳基和5-6元杂芳基，其中所述烷基、烷氧基、烯基、炔基、C3-6环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、3至6元杂环基、芳基和杂芳基中的一个或多个取代基所取代； R d and Re are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3 to 6 membered heterocyclyl, aryl and heteroaryl;

或者，Rd和Re与其相连的氮原子一起形成3-8元杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、二烷基氨基、烯基、炔基、C3-6环烷基、3-8元杂环基、芳基、杂芳基的一个或多个取代基所取代，所述环烷基和杂环基任选进一步被选自卤素、烷基、卤代烷基的一个或多个基团所取代；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;

Rf选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p为1或2；p is 1 or 2;

q为0至6的整数，优选1至6的整数，更优选1至4的整数。q is an integer of 0-6, preferably an integer of 1-6, and more preferably an integer of 1-4.

在另一个实施方案中，所述的通式(I)或通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
In another embodiment, the compound represented by the general formula (I) or the general formula (II) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中：in:

X1、X2、X3、X4各自独立地选自CH或N；优选地，X1为N且X2、X3、X4为CH，或者X2为N且X1、X3、X4为CH，或者X1、X2、X3、X4均为CH； X1 , X2 , X3 , X4 are each independently selected from CH or N; preferably, X1 is N and X2 , X3 , X4 are CH, or X2 is N and X1 , X3 , X4 are CH, or X1 , X2 , X3 , X4 are all CH;

Y选自NR5、CR5R6或SO2；Y is selected from NR 5 , CR 5 R 6 or SO 2 ;

R5选自氢、卤素、氨基、氧代基、氰基、C1-6烷基、C3-6环烷基、3-8元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)qNRdRe、C(O)Rf、C(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-S(O)pRf、-S(O)pNRdRe、-NRdC(O)Rf；所述C1-6烷基、C3-6环烷基、3-8元杂环基、C6-10芳基和5-6元杂芳基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基中的一个或多个取代基所取代； R5 is selected from hydrogen, halogen, amino, oxo, cyano, C1-6 alkyl, C3-6 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, -( CH2 ) qNRdRe , C(O) Rf , C(O) NRdRe , -C(O) NRf ( CH2 ) qNRdRe , -S(O) pRf , -S(O) pNRdRe , -NRdC (O) Rf ; the C1-6 alkyl, C3-6 cycloalkyl , 3-8 membered heterocyclyl, C6-10 aryl and 5-6 membered heteroaryl are optionally further substituted by one or more substituents selected from halogen, C1-6 alkyl and C1-6 haloalkyl;

R6选自氢、卤素、氨基和C1-6烷基； R6 is selected from hydrogen, halogen, amino and C1-6 alkyl;

或者，R5和R6与其相连的碳原子一起形成3-12元杂环基，优选3-6元杂环基； 所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、烯基、炔基、C3-6环烷基、3-8元杂环基、芳基、杂芳基的一个或多个取代基所取代；Alternatively, R 5 and R 6 together with the carbon atom to which they are attached form a 3-12 membered heterocyclic group, preferably a 3-6 membered heterocyclic group; The heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl;

Rd和Re各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、C3-6环烷基、3至6元杂环基、C6-10芳基和5-6元杂芳基，其中所述烷基、烷氧基、烯基、炔基、C3-6环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、3至6元杂环基、芳基和杂芳基中的一个或多个取代基所取代；R d and Re are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3 to 6 membered heterocyclyl, aryl and heteroaryl;

或者，Rd和Re与其相连的氮原子一起形成3-8元杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、二烷基氨基、烯基、炔基、C3-6环烷基、3-8元杂环基、芳基、杂芳基的一个或多个取代基所取代，所述环烷基和杂环基任选进一步被选自卤素、烷基、卤代烷基的一个或多个基团所取代；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl;

Rf选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p为1或2；p is 1 or 2;

q为1至6的整数，优选1至4的整数，更优选1或2；q is an integer from 1 to 6, preferably an integer from 1 to 4, more preferably 1 or 2;

n为0、1或2；n is 0, 1 or 2;

s为1或2；优选1；s is 1 or 2; preferably 1;

t为1或2；优选1；t is 1 or 2; preferably 1;

R2、R3、R4、m如通式(I)所定义；Q2如通式(II)所定义。R 2 , R 3 , R 4 and m are as defined in the general formula (I); Q 2 is as defined in the general formula (II).

在一个优选的实施方案中，根据本发明所述的通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：X1为N；X2、X3、X4为CH。In a preferred embodiment, the compound represented by general formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: X1 is N; X2 , X3 , X4 are CH.

在一个优选的实施方案中，根据本发明所述的通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：Y选自NR5；In a preferred embodiment, the compound represented by the general formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Y is selected from NR 5 ;

R5选自C1-6烷基、C1-6卤代烷基、C3-6环烷基、3-6元杂环基(例如氧杂环丁烷、氮杂环丁烷、吡咯烷基、呋喃基、哌啶基、哌嗪基、吡喃基)、苯基、5-6元杂芳基(例如吡啶基、噁唑基)、-C(O)Rf；所述C3-6环烷基、3-6元杂环基、苯基和5-6元杂芳基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基中的一个或多个取代基所取代； R 5 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl (e.g. oxetane, azetidine, pyrrolidinyl, furyl, piperidinyl, piperazinyl, pyranyl), phenyl, 5-6 membered heteroaryl (e.g. pyridyl, oxazolyl), -C(O)R f ; the C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl;

Rf选自C1-6烷基、C1-6卤代烷基。 Rf is selected from C1-6 alkyl, C1-6 haloalkyl.

在另一个优选的实施方案中，根据本发明所述的通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：Y选自CR5R6；In another preferred embodiment, the compound represented by the general formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Y is selected from CR 5 R 6 ;

R5选自氢、氰基、C1-6烷基、C1-6卤代烷基、C3-6环烷基、3-8元杂环基、苯基、5-6元杂芳基(例如咪唑基)、-(CH2)qNRdRe、-C(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-S(O)pNRdRe、-NRdC(O)Rf；R 5 is selected from hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl (e.g., imidazolyl), -(CH 2 ) q NR d R e , -C(O)NR d R e , -C(O)NR f (CH 2 ) q NR d R e , -S(O) p NR d R e , -NR d C(O) R f ;

R6选自氢、卤素、氨基和C1-6烷基； R6 is selected from hydrogen, halogen, amino and C1-6 alkyl;

Rd选自氢、C1-6烷基；R d is selected from hydrogen, C 1-6 alkyl;

Re选自氢、C1-6烷基、C1-6卤代烷基、C1-6羟烷基、C3-6环烷基、4至6元杂环基(例如吡喃基、氧杂环丁烷基、氮杂环丁烷基、哌啶基、哌嗪基、吡咯烷基)、苯基、5-6元杂芳基，所述C3-6环烷基、4至6元杂环基、苯基、5-6元杂芳基(例如吡啶基、噻唑基、咪唑基、吡唑基)任选进一步被选自卤素、C1-6烷基的一个或多个基团所取代；R is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 4 to 6 membered heterocyclyl (e.g. pyranyl, oxetanyl, azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl), phenyl, 5-6 membered heteroaryl, wherein the C 3-6 cycloalkyl, 4 to 6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl (e.g. pyridinyl, thiazolyl, imidazolyl, pyrazolyl) is optionally further substituted with one or more groups selected from halogen, C 1-6 alkyl;

Rd和Re与其相连的氮原子一起形成3-8元杂环基(例如氮杂环丁烷、吡咯烷基、吗啉基、哌啶基、哌嗪基、氮杂环辛烷)，所述3-8元杂环基任选进一步被选自C1-6烷基、C1-6卤代烷基、C1-6烷基氨基、C3-6环烷基、3-6元杂环基(例如氧杂环丁烷、哌嗪基、哌啶基、吗啉基)的一个或多个取代基所取代，所述C3-6环烷基、3-6元杂环基任选进一步被选自卤素、烷基、卤代烷基的一个或多个基团所取代；R d and Re together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group (e.g., azetidine, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, azoctane), wherein the 3-8 membered heterocyclic group is optionally further substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylamino, C 3-6 cycloalkyl, 3-6 membered heterocyclic group (e.g., oxetane, piperazinyl, piperidinyl, morpholinyl), wherein the C 3-6 cycloalkyl, 3-6 membered heterocyclic group is optionally further substituted with one or more substituents selected from halogen, alkyl, haloalkyl;

Rf为氢或C1-6烷基； Rf is hydrogen or C 1-6 alkyl;

p为1或2，优选2；p is 1 or 2, preferably 2;

q为0、1或2。q is 0, 1, or 2.

在另一个优选的实施方案中，根据本发明所述的通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：Y选自CR5R6；In another preferred embodiment, the compound represented by the general formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Y is selected from CR 5 R 6 ;

R5选自氢、氰基、C1-6烷基、C1-6卤代烷基、-(CH2)qNRdRe、-NRdC(O)Rf、-S(O)pNRdRe；R 5 is selected from hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -(CH 2 ) q NR d R e , -NR d C(O) R f , -S(O) p NR d R e ;

R6选自氢、卤素、氨基和C1-6烷基； R6 is selected from hydrogen, halogen, amino and C1-6 alkyl;

Rd选自氢、C1-6烷基；R d is selected from hydrogen, C 1-6 alkyl;

Re选自氢、C1-6烷基；R e is selected from hydrogen, C 1-6 alkyl;

Rf为氢或C1-6烷基； Rf is hydrogen or C 1-6 alkyl;

p为2；p is 2;

q为0或1；q is 0 or 1;

在另一个优选的实施方案中，根据本发明所述的通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、 或其混合物形式、或其可药用盐，其中：Y选自CR5R6；In another preferred embodiment, the compound represented by the general formula (III) according to the present invention or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Y is selected from CR 5 R 6 ;

R5选自氰基、C1-6烷基、C1-6卤代烷基、-(CH2)qNRdRe、-NRdC(O)Rf、-S(O)pNRdRe；R 5 is selected from cyano, C 1-6 alkyl, C 1-6 haloalkyl, -(CH 2 ) q NR d R e , -NR d C(O) R f , -S(O) p NR d R e ;

R6选自氢； R6 is selected from hydrogen;

Rd选自氢、C1-6烷基；R d is selected from hydrogen, C 1-6 alkyl;

Re选自氢、C1-6烷基；R e is selected from hydrogen, C 1-6 alkyl;

Rf为氢或C1-6烷基； Rf is hydrogen or C 1-6 alkyl;

p为2；p is 2;

q为0或1；q is 0 or 1;

在另一个优选的实施方案中，根据本发明所述的通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：Y选自SO2。In another preferred embodiment, the compound of formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Y is selected from SO 2 .

在另一个优选的实施方案中，根据本发明所述的通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：In another preferred embodiment, the compound represented by the general formula (III) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

Y选自CR5R6；Y is selected from CR 5 R 6 ;

R5和R6与其相连的碳原子一起形成氮杂环丁烷基、吡咯烷基、四氢咪唑基；所述氮杂环丁烷基、吡咯烷基、四氢咪唑基任选进一步被氧代基所取代。R 5 and R 6 together with the carbon atom to which they are attached form azetidinyl, pyrrolidinyl, tetrahydroimidazolyl; the azetidinyl, pyrrolidinyl, tetrahydroimidazolyl may be further substituted with oxo.

在另一个实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IIIA)或(IIIB)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，

In another embodiment, the compound represented by the general formula (I), general formula (II) or general formula (III) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IIIA) or (IIIB) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

其中：in:

X1、X2各自独立地选自CH或N；X 1 and X 2 are each independently selected from CH or N;

Y1选自N或CR6；Y 1 is selected from N or CR 6 ;

R6选自氢、卤素、氨基和C1-6烷基； R6 is selected from hydrogen, halogen, amino and C1-6 alkyl;

R7选自氢、C1-6烷基、C3-6环烷基、3至6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)qNRdRe，其中所述C1-6烷基、C3-6环烷基、3至6元杂环基、C6-10芳基、5-6元杂芳基任选进一步被选自卤素、羟基、巯基、C1-6烷基、C1-6卤代烷基、3至6元杂环基的一个或多个取代基所取代；R 7 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, 5 to 6 membered heteroaryl, -(CH 2 ) q NR d R e , wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, 5 to 6 membered heteroaryl is optionally further substituted with one or more substituents selected from halogen, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 haloalkyl, 3 to 6 membered heterocyclyl;

R8选自氢、C1-6烷基、C1-6卤代烷基；R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl;

或者，R7和R8与其相连的氮原子一起形成3-8元杂环基，优选6元杂环基，其中所述杂环基任选进一步被选自卤素、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷基氨基、C3-6环烷基、3-8元杂环基的一个或多个取代基所取代，其中所述C3-6环烷基、3-8元杂环基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基的一个或多个基团所取代；Alternatively, R7 and R8 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group, preferably a 6 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylamino, C3-6 cycloalkyl, 3-8 membered heterocyclic group, wherein the C3-6 cycloalkyl, 3-8 membered heterocyclic group is optionally further substituted with one or more groups selected from halogen, C1-6 alkyl, C1-6 haloalkyl;

Rd和Re各自独立地选自氢、C1-6烷基、C3-6环烷基、3至6元杂环基，其中所述C1-6烷基、C3-6环烷基、3至6元杂环基任选进一步被选自卤素的一个或多个取代基所取代；R d and Re are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl is optionally further substituted with one or more substituents selected from halogen;

或者，Rd和Re与其相连的氮原子一起形成3-6元杂环基，其中所述3-6元杂环基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基的一个或多个取代基所取代；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group is optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl;

R10选自C1-6烷基、C1-6卤代烷基；R 10 is selected from C 1-6 alkyl, C 1-6 haloalkyl;

q为1至4的整数，优选1或2；q is an integer from 1 to 4, preferably 1 or 2;

n为0、1或2；n is 0, 1 or 2;

R2、R3、R4、m如通式(I)所定义；Q2如通式(II)所定义。R 2 , R 3 , R 4 and m are as defined in the general formula (I); Q 2 is as defined in the general formula (II).

在一个优选的实施方案中，根据本发明所述的通式(IIIA)或(IIIB)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：X1为N，X2为CH。In a preferred embodiment, the compound represented by the general formula (IIIA) or (IIIB) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: X1 is N, and X2 is CH.

在另一个优选的实施方案中，根据本发明所述的通式(IIIA)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、 或其混合物形式、或其可药用盐，其中：In another preferred embodiment, the compound represented by the general formula (IIIA) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

Y1选自CR6；Y 1 is selected from CR 6 ;

R6选自氢、卤素、氨基和C1-6烷基。 R6 is selected from hydrogen, halogen, amino and C1-6 alkyl.

在另一个优选的实施方案中，根据本发明所述的通式(IIIA)或(IIIB)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：In another preferred embodiment, the compound represented by the general formula (IIIA) or (IIIB) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

Y1选自N。 Y1 is selected from N.

在另一个优选的实施方案中，根据本发明所述的通式(IIIA)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：In another preferred embodiment, the compound represented by general formula (IIIA) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

R7选自氢、C1-6烷基、C1-6卤代烷基、C1-6羟基烷基、C3-6环烷基、3至6元杂环基(例如氧杂环丁烷基、氮杂环丁烷基、吡喃基、呋喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基)、苯基、5-6元杂芳基(例如噻唑基、咪唑基、吡唑基、吡啶基)、-(CH2)qNRdRe，其中所述C3-6环烷基、3至6元杂环基、苯基、5-6元杂芳基任选进一步被选自卤素、C1-6烷基的一个或多个取代基所取代；R 7 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl (e.g. oxetanyl, azetidinyl, pyranyl, furanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl), phenyl, 5-6 membered heteroaryl (e.g. thiazolyl, imidazolyl, pyrazolyl, pyridinyl), -(CH 2 ) q NR d R e , wherein the C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl is optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl;

R8选自氢、C1-6烷基；R 8 is selected from hydrogen, C 1-6 alkyl;

Rd选自C1-6烷基；R d is selected from C 1-6 alkyl;

Re选自C1-6烷基；R e is selected from C 1-6 alkyl;

或者，Rd和Re与其相连的氮原子一起形成3-6元杂环基杂环基(例如氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基)；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclyl (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl);

q为2。q is 2.

在另一个优选的实施方案中，根据本发明所述的通式(IIIA)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：In another preferred embodiment, the compound represented by general formula (IIIA) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

R7和R8与其相连的氮原子一起形成3-8元杂环基(例如氮杂环丁烷基、氮杂环辛烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基、)，优选6元杂环基，其中所述杂环基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷基氨基、二C1-6烷基氨基、C3-6环烷基、3-8元杂环基(例如氧杂环丁烷基、哌啶基、哌嗪基、吗啉基)的一个或多个取代基所取代，其中所述C3-6环烷基、3-8元杂环基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基的一个或多个基团所取代。R 7 and R 8 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group (e.g. azetidinyl, azocanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl), preferably a 6-membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkylamino, diC 1-6 alkylamino, C 3-6 cycloalkyl, 3-8 membered heterocyclic group (e.g. oxetanyl, piperidinyl, piperazinyl, morpholinyl), wherein the C 3-6 cycloalkyl, 3-8 membered heterocyclic group is optionally further substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl.

在另一个优选的实施方案中，根据本发明所述的通式(IIIB)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：In another preferred embodiment, the compound represented by general formula (IIIB) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

R10选自C1-6烷基、C1-6卤代烷基。R 10 is selected from C 1-6 alkyl, C 1-6 haloalkyl.

在另一个实施方案中，所述的通式(I)、通式(II)或通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异 构体、或其混合物形式、或其可药用盐，其为通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
In another embodiment, the compound represented by the general formula (I), general formula (II) or general formula (III) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereoisomers isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IIIC) or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中：in:

X1、X2各自独立地选自CH或N；X 1 and X 2 are each independently selected from CH or N;

Y2选自NR11、CR11R12、SO2；Y 2 is selected from NR 11 , CR 11 R 12 , SO 2 ;

R12选自氢、卤素、氨基和C1-6烷基；R 12 is selected from hydrogen, halogen, amino and C 1-6 alkyl;

R11选自氢、卤素、氧代基、硫代基、氰基、羟基、巯基、C1-6烷基、C3-6环烷基、3-8元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)qNRdRe、-C(O)NRdRe、-S(O)pNRdRe和-NRdC(O)Rf中的一个或多个取代基所取代；所述C1-6烷基、C3-6环烷基、3-8元杂环基、C6-10芳基和5-6元杂芳基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基中的一个或多个取代基所取代；R 11 is substituted by one or more substituents selected from hydrogen, halogen, oxo, thio, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -(CH 2 ) q NR d R e , -C(O)NR d R e , -S(O) p NR d R e and -NR d C(O) R f ; the C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl are optionally further substituted by one or more substituents selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl;

或者，R11和R12与其相连的碳原子一起形成3-12元杂环基，优选3-6元杂环基；所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、烯基、炔基、C3-6环烷基、3-8元杂环基、芳基、杂芳基的一个或多个取代基所取代；Alternatively, R 11 and R 12 together with the carbon atom to which they are attached form a 3-12-membered heterocyclic group, preferably a 3-6-membered heterocyclic group; the heterocyclic group is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8-membered heterocyclic group, aryl, heteroaryl;

Rd和Re各自独立地选自氢和C1-6烷基；R d and Re are each independently selected from hydrogen and C 1-6 alkyl;

Rf选自C1-6烷基； Rf is selected from C 1-6 alkyl;

p为1或2；p is 1 or 2;

q为0至4的整数，优选0至2的整数；q is an integer from 0 to 4, preferably an integer from 0 to 2;

R2、R3、R4、m如通式(I)所定义；Q2、n如通式(II)所定义。R 2 , R 3 , R 4 and m are as defined in the general formula (I); Q 2 and n are as defined in the general formula (II).

在另一个实施方案中，所述的通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，In another embodiment, the compound represented by the general formula (II) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

Q1选自NRaRb；Q 1 is selected from NR a R b ;

Ra选自氢和C1-6烷基；R a is selected from hydrogen and C 1-6 alkyl;

Rb选自C1-6烷基，所述C1-6烷基任选进一步被选自-NRdRe、-NRdC(O)Rf、-C(O)NRdRe的取代基所取代； R b is selected from C 1-6 alkyl, wherein the C 1-6 alkyl is optionally further substituted by a substituent selected from -NR d R e , -NR d C(O)R f , -C(O)NR d R e ;

Rd和Re各自独立地选自氢和C1-6烷基；R d and Re are each independently selected from hydrogen and C 1-6 alkyl;

或者Rd和Re与其相连的氮原子一起形成5-6元杂环基(例如吡咯烷基)，所述5-6元杂环基任选进一步被选自卤素、氨基、氧代基、C1-6烷基的取代基所取代；Or R d and Re together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group (e.g., pyrrolidinyl), wherein the 5-6 membered heterocyclic group is optionally further substituted by a substituent selected from halogen, amino, oxo, C 1-6 alkyl;

Rf选自C1-6烷基。 Rf is selected from C1-6 alkyl.

在另一个实施方案中，所述的通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，In another embodiment, the compound represented by the general formula (II) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

L为键；L is a key;

Q1选自NRaRb；Q 1 is selected from NR a R b ;

Ra选自氢和C1-6烷基；R a is selected from hydrogen and C 1-6 alkyl;

Rb选自C1-6烷基，优选C1-4烷基，所述烷基任选进一步被选自-NRdRe、-NRdC(O)Rf、-C(O)NRdRe的取代基所取代；R b is selected from C 1-6 alkyl, preferably C 1-4 alkyl, wherein the alkyl is optionally further substituted by a substituent selected from -NR d R e , -NR d C(O)R f , -C(O)NR d R e ;

Rd和Re各自独立地选自氢和C1-6烷基；R d and Re are each independently selected from hydrogen and C 1-6 alkyl;

或者Rd和Re与其相连的氮原子一起形成5-6元杂环基(例如吡咯烷基)，所述5-6元杂环基任选进一步被选自卤素、氨基、氧代基、C1-6烷基的取代基所取代，优选被氧代基取代；or R d and Re together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group (e.g., pyrrolidinyl), wherein the 5-6 membered heterocyclic group is optionally further substituted by a substituent selected from halogen, amino, oxo, C 1-6 alkyl, preferably substituted by oxo;

Rf选自C1-6烷基。 Rf is selected from C1-6 alkyl.

在另一个实施方案中，所述的通式(I)或通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
In another embodiment, the compound represented by the general formula (I) or the general formula (II) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is the compound represented by the general formula (IV) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein,

其中：in:

X1、X2各自独立地选自CH或N；X 1 and X 2 are each independently selected from CH or N;

Y3、Y4、Y5、Y6各自独立地选自CH或N，优选均为CH，或者其中之一为N，其余为CH，或者其中之二为N，其余为CH；Y 3 , Y 4 , Y 5 , and Y 6 are each independently selected from CH or N, preferably all are CH, or one of them is N and the others are CH, or two of them are N and the others are CH;

每个R13a各自独立地选自氢、卤素、C1-6烷基；s为0、1、2、3或4，优选0、1或2； Each R 13a is independently selected from hydrogen, halogen, C 1-6 alkyl; s is 0, 1, 2, 3 or 4, preferably 0, 1 or 2;

R13b选自氢、卤素、氨基、氰基、C1-6烷基、C3-6环烷基、3-8元杂环基、-C(O)NRdRe、-C(O)NRf(CH2)qNRdRe；R 13b is selected from hydrogen, halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -C(O)NR d R e , -C(O)NR f (CH 2 ) q NR d R e ;

Rd和Re各自独立地选自氢、C1-6烷基、C3-6环烷基，所述；R d and Re are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, said;

或者Rd和Re与其相连的氮原子一起形成5-6元杂环基，所述5-6元杂环基任选进一步被选自卤素、氨基、氧代基、C1-6烷基、5-6元杂环基的取代基所取代；or R d and Re together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally further substituted by a substituent selected from halogen, amino, oxo, C 1-6 alkyl, and 5-6 membered heterocyclic group;

Rf选自氢和C1-6烷基； Rf is selected from hydrogen and C 1-6 alkyl;

q为1至4的整数，优选1或2；q is an integer from 1 to 4, preferably 1 or 2;

R2、R3、R4、m如通式(I)所定义；Q2、n如通式(II)所定义。R 2 , R 3 , R 4 and m are as defined in the general formula (I); Q 2 and n are as defined in the general formula (II).

在一个优选的实施方案中，根据本发明所述的通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Y3、Y4、Y5、Y6为CH。In a preferred embodiment, according to the compound of formula (IV) of the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, Y 3 , Y 4 , Y 5 , Y 6 are CH.

在另一个优选的实施方案中，根据本发明所述的通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，X1为N，X2为CH。In another preferred embodiment, according to the compound represented by general formula (IV) of the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein X1 is N and X2 is CH.

在另一个优选的实施方案中，根据本发明所述的通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R13b选自-C(O)NRdRe In another preferred embodiment, the compound represented by the general formula (IV) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 13b is selected from -C(O)NR d R e

Rd选自氢、C1-6烷基；R d is selected from hydrogen, C 1-6 alkyl;

Re选自氢、C1-6烷基、C3-6环烷基；所述C3-6环烷基任选进一步被卤素取代；R e is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl; the C 3-6 cycloalkyl is optionally further substituted by halogen;

或者Rd和Re与其相连的氮原子一起形成5-6元杂环基(例如氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基)，所述5-6元杂环基任选进一步被5-6元杂环基(例如吡咯烷基、哌啶基、哌嗪基、吗啉基)所取代。Alternatively, R d and Re together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl), which is optionally further substituted by a 5-6 membered heterocyclic group (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl).

在另一个优选的实施方案中，根据本发明所述的通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R13b选自-C(O)NRf(CH2)qNRdRe；In another preferred embodiment, the compound represented by the general formula (IV) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 13b is selected from -C(O)NR f (CH 2 ) q NR d R e ;

Rd选自氢、C1-6烷基，优选C1-6烷基；R d is selected from hydrogen, C 1-6 alkyl, preferably C 1-6 alkyl;

Re选自C1-6烷基；R e is selected from C 1-6 alkyl;

或者Rd和Re与其相连的氮原子一起形成5-6元杂环基(例如氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、吗啉基)；or R d and Re together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group (e.g., azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl);

Rf选自氢和C1-6烷基，优选氢； Rf is selected from hydrogen and C 1-6 alkyl, preferably hydrogen;

q为1至4的整数，优选2。q is an integer of 1 to 4, preferably 2.

在另一个实施方案中，所述的通式(I)或通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其 混合物形式、或其可药用盐，其中，Q1选自8-10元稠杂环基，优选 其任选进一步被选自C1-6烷基和C1-6卤代烷基的取代基所取代。In another embodiment, the compound represented by the general formula (I) or the general formula (II) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or its mixture form, or a pharmaceutically acceptable salt thereof, wherein Q 1 is selected from 8-10 membered fused heterocyclic groups, preferably It is optionally further substituted with a substituent selected from C 1-6 alkyl and C 1-6 haloalkyl.

在另一个实施方案中，所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another embodiment, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

其中：in:

R1为 R1 is

L选自键、亚烷基、或-C(O)-；L is selected from a bond, an alkylene group, or -C(O)-;

环A选自C6-10芳基、5至10元杂芳基，优选苯基、萘基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吲哚基、吲唑基、喹啉基、喹喔啉基、喹唑啉基、吡啶并吡咯基、吡啶并咪唑基、苯并咪唑基、苯并吡唑基、；其任选被一个或多个Q基团取代；Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, preferably phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, quinolyl, quinoxalinyl, quinazolinyl, pyridopyrrolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, which is optionally substituted by one or more Q groups;

Q选自卤素、羟基、巯基、氰基、C1-6烷基、C1-6卤代烷基、-(CH2)qNRaRb；Q is selected from halogen, hydroxyl, mercapto, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -(CH 2 ) q NR a R b ;

Ra和Rb各自独立地选自氢和C1-6烷基；R a and R b are each independently selected from hydrogen and C 1-6 alkyl;

q为0-4的整数，优选0-2的整数。q is an integer of 0-4, preferably an integer of 0-2.

在另一个实施方案中，所述的通式(I)、通式(II)、通式(III)、(IIIA)、(IIIB)、(IIIC)、通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，In another embodiment, the compound represented by the general formula (I), general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

其中，R2选自氢和C1-6烷基。Wherein, R2 is selected from hydrogen and C1-6 alkyl.

在另一个实施方案中，所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R1和R2与其相连的氮原子一起形成5-10元杂环基或5-10元杂芳基，优选8-10元杂环基，更优选其任选进一步被选自卤素、氨基、氰基、羟基、巯基、氧代基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、-(CH2)qNRaRb的一个或多个取代基所取代；In another embodiment, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 together with the nitrogen atom to which they are connected form a 5-10 membered heterocyclic group or a 5-10 membered heteroaryl group, preferably an 8-10 membered heterocyclic group, more preferably which is optionally further substituted by one or more substituents selected from halogen, amino, cyano, hydroxyl, mercapto, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH 2 ) q NR a R b ;

q为1至4的整数，优选1或2；q is an integer from 1 to 4, preferably 1 or 2;

Ra和Rb各自独立地选自氢或C1-6烷基。 Ra and Rb are each independently selected from hydrogen or C1-6 alkyl.

在另一个实施方案中，所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、 或其可药用盐，其中，R1和R2与其相连的氮原子一起形成杂环基，所述杂环基选自： 优选为所述杂环基任选进一步被选自卤素、氨基、氰基、羟基、巯基、氧代基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、-(CH2)qNRaRb的一个或多个取代基所取代；In another embodiment, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic group selected from: Preferably The heterocyclic group is optionally further substituted by one or more substituents selected from halogen, amino, cyano, hydroxyl, mercapto, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH 2 ) q NR a R b ;

q为1至4的整数，优选1或2；q is an integer from 1 to 4, preferably 1 or 2;

Ra和Rb各自独立地选自氢或C1-6烷基。 Ra and Rb are each independently selected from hydrogen or C1-6 alkyl.

在另一个实施方案中，所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R1和R2与其相连的氮原子一起形成杂环基，所述杂环基选自：所述杂环基任选进一步被选自C1-6烷氧基、C1-6卤代烷氧基、-(CH2)qNRaRb的一个或多个取代基所取代；In another embodiment, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic group, and the heterocyclic group is selected from: The heterocyclic group is optionally further substituted by one or more substituents selected from C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH 2 ) q NR a R b ;

q为1或2；q is 1 or 2;

Ra和Rb各自独立地选自氢或C1-6烷基。 Ra and Rb are each independently selected from hydrogen or C1-6 alkyl.

在另一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：In another specific embodiment, the compound represented by the general formula (I) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

R1为 R1 is

R2为氢； R2 is hydrogen;

其中：in:

L选自-CH2-、-C(O)-；L is selected from -CH 2 -, -C(O)-;

环A选自苯基，所述苯基任选进一步被-(CH2)qNRaRb所取代；Ring A is selected from phenyl, which is optionally further substituted with -(CH 2 ) q NR a R b ;

Ra和Rb各自独立地选自氢或C1-6烷基； R a and R b are each independently selected from hydrogen or C 1-6 alkyl;

q为1。q is 1.

在另一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：In another specific embodiment, the compound represented by the general formula (I) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

R1为 R1 is

R2为氢； R2 is hydrogen;

其中：in:

L为键；L is a key;

环A选自C6-10芳基或5至10元杂芳基，优选5至10元杂芳基；所述C6-10芳基或5至10元杂芳基任选进一步被选自卤素、C1-6烷基、C1-6卤素烷基、-(CH2)qNRaRb的一个或多个基团所取代；Ring A is selected from C 6-10 aryl or 5- to 10-membered heteroaryl, preferably 5- to 10-membered heteroaryl; the C 6-10 aryl or 5- to 10-membered heteroaryl is optionally further substituted by one or more groups selected from halogen, C 1-6 alkyl, C 1-6 halogenalkyl, -(CH 2 ) q NR a R b ;

Ra和Rb各自独立地选自氢或C1-6烷基；R a and R b are each independently selected from hydrogen or C 1-6 alkyl;

q为1。q is 1.

在另一个具体的实施方案中，根据本发明所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中：In another specific embodiment, the compound represented by the general formula (I) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein:

R1为 R1 is

R2为氢； R2 is hydrogen;

其中：in:

L为键；L is a key;

环A选自环A任选进一步被选自卤素、C1-6烷基、C1-6卤素烷基、-(CH2)qNRaRb的一个或多个基团所取代；Ring A is selected from Ring A is optionally further substituted by one or more groups selected from halogen, C 1-6 alkyl, C 1-6 halogenalkyl, -(CH 2 ) q NR a R b ;

Ra和Rb各自独立地选自氢或C1-6烷基；R a and R b are each independently selected from hydrogen or C 1-6 alkyl;

q为1。q is 1.

在另一个实施方案中，所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(V)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
In another embodiment, the compound represented by the general formula (I) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (V) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

其中：in:

环M选自5-6元杂环基，优选6元杂环基；Ring M is selected from 5-6 membered heterocyclic groups, preferably 6 membered heterocyclic groups;

Y7选自NR13、CR13R14、SO2；Y 7 is selected from NR 13 , CR 13 R 14 , SO 2 ;

R14选自氢、卤素、氨基和C1-6烷基；R 14 is selected from hydrogen, halogen, amino and C 1-6 alkyl;

R13选自氢、卤素、氧代基、硫代基、氰基、羟基、巯基、C1-6烷基、C3-6环烷基、3-8元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)qNRdRe、-C(O)NRdRe、-S(O)pNRdRe和-NRdC(O)Rf中的一个或多个取代基所取代；所述C1-6烷基、C3-6环烷基、3-8元杂环基、C6-10芳基和5-6元杂芳基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基中的一个或多个取代基所取代；R 13 is substituted by one or more substituents selected from hydrogen, halogen, oxo, thio, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -(CH 2 ) q NR d R e , -C(O)NR d R e , -S(O) p NR d R e and -NR d C(O) R f ; the C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl are optionally further substituted by one or more substituents selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl;

或者，R13和R14与其相连的碳原子一起形成3-12元杂环基，优选3-6元杂环基；所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、烯基、炔基、C3-6环烷基、3-8元杂环基、芳基、杂芳基的一个或多个取代基所取代；Alternatively, R 13 and R 14 together with the carbon atom to which they are attached form a 3-12 membered heterocyclic group, preferably a 3-6 membered heterocyclic group; the heterocyclic group is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl;

Rd和Re各自独立地选自氢和C1-6烷基；R d and Re are each independently selected from hydrogen and C 1-6 alkyl;

Rf选自C1-6烷基； Rf is selected from C 1-6 alkyl;

p为1或2；p is 1 or 2;

q为0至4的整数，优选0至2的整数；q is an integer from 0 to 4, preferably an integer from 0 to 2;

R2、R3、R4、m如通式(I)所定义；Q2、n如通式(II)所定义。R 2 , R 3 , R 4 and m are as defined in the general formula (I); Q 2 and n are as defined in the general formula (II).

在一个优选的实施方案中，根据本发明所述的通式(V)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，环M为 In a preferred embodiment, the compound represented by the general formula (V) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring M is

在一个优选的实施方案中，根据本发明所述的通式(V)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Y7为CR13R14；In a preferred embodiment, the compound represented by general formula (V) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein Y 7 is CR 13 R 14 ;

R14选自氢或C1-6烷基，优选氢； R 14 is selected from hydrogen or C 1-6 alkyl, preferably hydrogen;

R13选自-C(O)NRdRe；R 13 is selected from -C(O)NR d R e ;

Rd和Re各自独立地选自氢和C1-6烷基。R d and Re are each independently selected from hydrogen and C 1-6 alkyl.

在另一个实施方案中，所述的通式(I)、通式(II)、通式(III)、(IIIA)、(IIIB)、(IIIC)、通式(IV)、通式(V)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R3选自C1-6烷基或C1-6卤代烷基，特别是甲基、乙基、正丙基、异丙基。In another embodiment, the compound represented by the general formula (I), general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV), general formula (V) or its stereoisomers, tautomers, racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R3 is selected from C1-6 alkyl or C1-6 haloalkyl, in particular methyl, ethyl, n-propyl, isopropyl.

在另一个实施方案中，所述的通式(I)、通式(II)、通式(III)、(IIIA)、(IIIB)、(IIIC)、通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，每个R4各自独立地选自氢、卤素、C1-6烷基、C1-6卤代烷基；m为0或1。In another embodiment, the compound represented by the general formula (I), general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomers, tautomers, mesomorphs, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein each R 4 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl; m is 0 or 1.

在另一个实施方案中，所述的通式(I)、通式(II)、通式(III)、(IIIA)、(IIIB)、(IIIC)、通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R2为氢或C1-6烷基，优选氢。In another embodiment, the compound represented by the general formula (I), general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomers, tautomers, racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R2 is hydrogen or C1-6 alkyl, preferably hydrogen.

在另一个实施方案中，所述的通式通式(II)、通式(III)、(IIIA)、(IIIB)、(IIIC)、通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，每个Q2各自独立地选自氢、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氧代基、氰基、(CH2)qC(O)NRaRb，所述C1-6烷基任选进一步被NRaRb取代；In another embodiment, the compound represented by the general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein each Q 2 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, (CH 2 ) q C(O)NR a R b , and the C 1-6 alkyl is optionally further substituted by NR a R b ;

Ra和Rb各自独立地选自氢或C1-6烷基；R a and R b are each independently selected from hydrogen or C 1-6 alkyl;

q为0至6的整数；q is an integer from 0 to 6;

n为0至4的整数，优选0至2的整数。n is an integer of 0-4, preferably an integer of 0-2.

在另一个实施方案中，所述的通式通式(II)、通式(III)、(IIIA)、(IIIB)、(IIIC)、通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，每个Q2各自独立地选自氢、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氧代基、氰基、-C(O)NRaRb、-CH2-NRaRb；In another embodiment, the compound represented by the general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein each Q 2 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, oxo, cyano, -C(O)NR a R b , -CH 2 -NR a R b ;

Ra和Rb各自独立地选自氢或C1-6烷基。 Ra and Rb are each independently selected from hydrogen or C1-6 alkyl.

在另一个实施方案中，所述的通式通式(II)、通式(III)、(IIIA)、(IIIB)、(IIIC)、通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，n为1或2，优选1。In another embodiment, the compound represented by the general formula (II), general formula (III), (IIIA), (IIIB), (IIIC), general formula (IV) or its stereoisomers, tautomers, racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein n is 1 or 2, preferably 1.

本发明典型的化合物包括但不限于：





















Typical compounds of the present invention include, but are not limited to:





















本发明还涉及根据本发明所述的通式(I)所示的化合物或其立体异构体、互 变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：
The present invention also relates to the compounds represented by the general formula (I) according to the present invention or their stereoisomers, A method for preparing a variant isomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

在碱性条件下，在缩合剂存在下，通式(IA)的化合物与通式(IB)的化合物发生缩合反应，得到通式(I)所示的化合物；Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IA) reacts with the compound of general formula (IB) to obtain a compound represented by general formula (I);

所述碱优选有机碱或无机碱，无机碱优选碳酸钾、碳酸铯、碳酸钠，有机碱优选DMAP(4-二甲氨基吡啶)、三乙胺、DIPEA(二异丙基乙胺)；The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (diisopropylethylamine);

所述缩合剂优选EDCI(N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐)、DCC(二环己基碳二亚胺)、CDI(N,N'-羰基二咪唑)、HOBt(1-羟基苯并三氮唑)、HOAT(1-羟基-7-偶氮苯并三氮唑)、HATU(O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、TBTU(O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯)、HBTU(苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯)、PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)；The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

反应优选在溶剂中进行，所述溶剂优选二氯甲烷、DMF(二甲基甲酰胺)、乙腈和甲苯；The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

其中：R1、R2、R3、R4、m如通式(I)所定义。wherein: R 1 , R 2 , R 3 , R 4 and m are as defined in the general formula (I).

本发明还涉及根据本发明所述的通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：
The present invention also relates to a method for preparing the compound represented by the general formula (II) according to the present invention or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

在碱性条件下，在缩合剂存在下，通式(IA)的化合物与通式(IIB)的化合物发生缩合反应，得到通式(II)所示的化合物；Under alkaline conditions, in the presence of a condensation agent, the compound of general formula (IA) undergoes a condensation reaction with the compound of general formula (IIB) to obtain a compound represented by general formula (II);

所述碱优选有机碱或无机碱，无机碱优选碳酸钾、碳酸铯、碳酸钠，有机碱优选DMAP(4-二甲氨基吡啶)、三乙胺、DIPEA(二异丙基乙胺)； The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (diisopropylethylamine);

所述缩合剂优选EDCI(N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐)、DCC(二环己基碳二亚胺)、CDI(N,N'-羰基二咪唑)、HOBt(1-羟基苯并三氮唑)、HOAT(1-羟基-7-偶氮苯并三氮唑)、HATU(O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、TBTU(O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯)、HBTU(苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯)、PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)；The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

反应优选在溶剂中进行，所述溶剂优选二氯甲烷、DMF(二甲基甲酰胺)、乙腈和甲苯；The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

其中：R2、R3、R4、L、X1～X4、Q1、Q2、m、n如通式(II)所定义。wherein: R 2 , R 3 , R 4 , L, X 1 to X 4 , Q 1 , Q 2 , m and n are as defined in the general formula (II).

本发明还涉及根据本发明所述的通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：
The present invention also relates to a method for preparing the compound represented by the general formula (III) according to the present invention or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

在碱性条件下，在缩合剂存在下，通式(IA)的化合物与通式(IIIb)的化合物发生缩合反应，得到通式(III)所示的化合物；Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IA) undergoes a condensation reaction with the compound of general formula (IIIb) to obtain a compound represented by general formula (III);

所述碱优选有机碱或无机碱，无机碱优选碳酸钾、碳酸铯、碳酸钠，有机碱优选DMAP(4-二甲氨基吡啶)、三乙胺、DIPEA(二异丙基乙胺)；The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (diisopropylethylamine);

所述缩合剂优选EDCI(N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐)、DCC(二环己基碳二亚胺)、CDI(N,N'-羰基二咪唑)、HOBt(1-羟基苯并三氮唑)、HOAT(1-羟基-7-偶氮苯并三氮唑)、HATU(O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、TBTU(O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯)、HBTU(苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯)、PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)；The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

反应优选在溶剂中进行，所述溶剂优选二氯甲烷、DMF(二甲基甲酰胺)、乙腈和甲苯；The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

其中：R2、R3、R4、X1～X4、Y、Q2、m、n如通式(III)所定义。wherein: R 2 , R 3 , R 4 , X 1 to X 4 , Y, Q 2 , m and n are as defined in the general formula (III).

本发明还涉及根据本发明所述的通式(IIIA)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的方法，其包括以下步骤：
The present invention also relates to a method for preparing a compound represented by general formula (IIIA) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

在碱性条件下，在缩合剂存在下，通式(IIIAa)的化合物与通式(IIIAb)的化合物发生缩合反应，得到通式(IIIA)所示的化合物；Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IIIAa) undergoes a condensation reaction with the compound of general formula (IIIAb) to obtain a compound represented by general formula (IIIA);

所述碱优选有机碱或无机碱，无机碱优选碳酸钾、碳酸铯、碳酸钠，有机碱优选DMAP(4-二甲氨基吡啶)、三乙胺、DIPEA(二异丙基乙胺)；The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (diisopropylethylamine);

所述缩合剂优选EDCI(N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐)、DCC(二环己基碳二亚胺)、CDI(N,N'-羰基二咪唑)、HOBt(1-羟基苯并三氮唑)、HOAT(1-羟基-7-偶氮苯并三氮唑)、HATU(O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、TBTU(O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯)、HBTU(苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯)、PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)；The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

反应优选在溶剂中进行，所述溶剂优选二氯甲烷、DMF(二甲基甲酰胺)、乙腈和甲苯；The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

其中：R2、R3、R4、R7、R8、X1、X2、Y1、Q2、m、n如通式(IIIA)所定义。wherein: R 2 , R 3 , R 4 , R 7 , R 8 , X 1 , X 2 , Y 1 , Q 2 , m and n are as defined in the general formula (IIIA).

本发明还涉及根据本发明所述的通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：
The present invention also relates to a method for preparing the compound represented by general formula (IIIC) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

在碱性条件下，在缩合剂存在下，通式(IA)的化合物与通式(IIICb)的化合物发生缩合反应，得到通式(IIIC)所示的化合物；Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IA) undergoes a condensation reaction with the compound of general formula (IIICb) to obtain a compound represented by general formula (IIIC);

所述碱优选有机碱或无机碱，无机碱优选碳酸钾、碳酸铯、碳酸钠，有机碱优选DMAP(4-二甲氨基吡啶)、三乙胺、DIPEA(二异丙基乙胺)；The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (diisopropylethylamine);

所述缩合剂优选EDCI(N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐)、DCC(二环己基碳二亚胺)、CDI(N,N'-羰基二咪唑)、HOBt(1-羟基苯并三氮唑)、HOAT(1-羟基-7-偶氮苯并三氮唑)、HATU(O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六 氟磷酸酯)、TBTU(O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯)、HBTU(苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯)、PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)；The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexachloride) fluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

反应优选在溶剂中进行，所述溶剂优选二氯甲烷、DMF(二甲基甲酰胺)、乙腈和甲苯；The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

其中：R2、R3、R4、X1、X2、Y2、Q2、m、n如通式(IIIC)所定义。wherein: R 2 , R 3 , R 4 , X 1 , X 2 , Y 2 , Q 2 , m and n are as defined in the general formula (IIIC).

本发明还涉及根据本发明所述的通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的制备方法，其包括以下步骤：
The present invention also relates to a method for preparing the compound represented by the general formula (IV) according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which comprises the following steps:

在碱性条件下，在缩合剂存在下，通式(IA)的化合物与通式(IVb)的化合物发生缩合反应，得到通式(IV)所示的化合物；Under alkaline conditions, in the presence of a condensation agent, the compound of general formula (IA) undergoes a condensation reaction with the compound of general formula (IVb) to obtain a compound represented by general formula (IV);

所述碱优选有机碱或无机碱，无机碱优选碳酸钾、碳酸铯、碳酸钠，有机碱优选DMAP(4-二甲氨基吡啶)、三乙胺、DIPEA(二异丙基乙胺)；The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP (4-dimethylaminopyridine), triethylamine, DIPEA (diisopropylethylamine);

所述缩合剂优选EDCI(N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐)、DCC(二环己基碳二亚胺)、CDI(N,N'-羰基二咪唑)、HOBt(1-羟基苯并三氮唑)、HOAT(1-羟基-7-偶氮苯并三氮唑)、HATU(O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、TBTU(O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯)、HBTU(苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯)、PyBOP(1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐)；The condensing agent is preferably EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), CDI (N,N'-carbonyldiimidazole), HOBt (1-hydroxybenzotriazole), HOAT (1-hydroxy-7-azobenzotriazole), HATU (O-(7-nitrobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate), TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate), PyBOP (1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate);

反应优选在溶剂中进行，所述溶剂优选二氯甲烷、DMF(二甲基甲酰胺)、乙腈和甲苯；The reaction is preferably carried out in a solvent, preferably dichloromethane, DMF (dimethylformamide), acetonitrile and toluene;

其中：R2、R3、R4、R13a、R13b、X1、X2、Y3～Y6、Q2、m、n、s如通式(IV)所定义。wherein: R 2 , R 3 , R 4 , R 13a , R 13b , X 1 , X 2 , Y 3 to Y 6 , Q 2 , m, n and s are as defined in the general formula (IV).

本发明另外涉及一种药物组合物，其包含根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及一种或多种药学上可接受的载体或赋形剂。The present invention further relates to a pharmaceutical composition comprising a compound according to the present invention or its stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

本发明进一步涉及根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据包含其的药物组合物在制备ATR激酶抑制剂中的用途。 The present invention further relates to the use of the compound according to the present invention or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt or a pharmaceutical composition containing the same in the preparation of ATR kinase inhibitors.

本发明进一步涉及根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据包含其的药物组合物在制备用于治疗ATR激酶介导的疾病的药物中的用途，所述疾病优选黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌)、肾癌、膀胱癌、胆囊癌、乳腺癌、宫颈癌、卵巢癌、前列腺癌、皮肤癌、神经胶质瘤、肉瘤、骨癌、子宫癌、子宫内膜癌、甲状腺癌、头颈肿瘤、白血病(包括急性淋巴细胞白血病(ALL)、慢性髓细胞源性白血病(CML)以及急性髓细胞白血病(AML)等)、多发性骨髓瘤和淋巴癌。The present invention further relates to the use of the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, in the preparation of a medicament for treating ATR kinase-mediated diseases, preferably melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar carcinoma), kidney cancer, bladder cancer, gallbladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck tumors, leukemia (including acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML)), multiple myeloma and lymphoma.

本发明还涉及根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据包含其的药物组合物，其用作ATR激酶抑制剂。The present invention also relates to the compounds according to the present invention or their stereoisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts or to pharmaceutical compositions comprising them, for use as ATR kinase inhibitors.

本发明还涉及根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据包含其的药物组合物，其用于治疗ATR激酶介导的疾病，所述疾病优选黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌)、肾癌、膀胱癌、胆囊癌、乳腺癌、宫颈癌、卵巢癌、前列腺癌、皮肤癌、神经胶质瘤、肉瘤、骨癌、子宫癌、子宫内膜癌、甲状腺癌、头颈肿瘤、白血病(包括急性淋巴细胞白血病(ALL)、慢性髓细胞源性白血病(CML)以及急性髓细胞白血病(AML)等)、多发性骨髓瘤和淋巴癌。The present invention also relates to the compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating ATR kinase-mediated diseases, preferably melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar carcinoma), kidney cancer, bladder cancer, gallbladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck tumors, leukemia (including acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML)), multiple myeloma and lymphoma.

本发明还涉及一种抑制ATR激酶的方法，其包括向有需要的受试者施用有效量的根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据包含其的药物组合物。The present invention also relates to a method for inhibiting ATR kinase, which comprises administering to a subject in need thereof an effective amount of a compound according to the present invention or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

本发明还涉及一种治疗ATR激酶介导的疾病的方法，其包括向有需要的患者施用治疗有效量的根据本发明所述的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据包含其的药物组合物，其中所述疾病优选黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌)、肾癌、膀胱癌、胆囊癌、乳腺癌、宫颈癌、卵巢癌、前列腺癌、皮肤癌、神经胶质瘤、肉瘤、骨癌、子宫癌、子宫内膜癌、甲状腺癌、头颈肿瘤、白血病(包括急性淋巴细胞白血病(ALL)、慢性髓细胞源性白血病(CML)以及急性髓细胞白血病(AML)等)、多发性骨髓瘤和淋巴癌。The present invention also relates to a method for treating an ATR kinase-mediated disease, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to the present invention or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising the same, wherein the disease is preferably melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar carcinoma), kidney cancer, bladder cancer, gallbladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck tumors, leukemia (including acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML)), multiple myeloma and lymphoma.

按照本发明所属领域的常规方法，本发明化合物可以与酸生成药学上可接受的酸式加成盐。所述酸包括无机酸和有机酸，特别优选盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三 氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。According to the conventional method in the field of the present invention, the compound of the present invention can be reacted with an acid to form a pharmaceutically acceptable acid addition salt. The acid includes inorganic acids and organic acids, and particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tris(2-hydroxy-1-nitropropenesulfonic acid) and 1-(2-hydroxy-1-nitropropenesulfonic acid). Fluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

按照本发明所属领域的常规方法，本发明通式化合物可以与碱生成药学上可接受的碱式加成盐。所述碱包括无机碱和有机碱，可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等，可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。According to the conventional method in the field of the present invention, the compound of the general formula of the present invention can form a pharmaceutically acceptable basic addition salt with a base. The base includes an inorganic base and an organic base, and the acceptable organic base includes diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc., and the acceptable inorganic base includes aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide, etc.

含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, colorants and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain active ingredients and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, corn starch or alginic acid; binders such as starch, gelatin, polyvinyl pyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release action over a longer period of time. For example, water soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or time extending materials such as ethylcellulose, cellulose acetate butyrate may be used.

也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。Oral preparations may also be provided in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oily vehicle such as peanut oil, liquid paraffin or olive oil.

水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadeca乙基eneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing agents or wetting agents, which may be naturally occurring phosphatides such as lecithin, or condensation products of alkylene oxides with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain fatty alcohols, for example heptadecaethyleneoxy cetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, for example polyethylene oxide sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene oxide anhydrosorbitan monooleate. The aqueous suspension may also contain one or more preservatives, for example ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, for example sucrose, saccharin or aspartame.

油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspension may contain a thickener such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant such as butylated hydroxyanisole or alpha-tocopherol.

通过加入水，适用于制备水混悬液的可分散粉末和颗粒可以提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润 剂和悬浮剂如上所述。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. The activators and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions may be preserved by adding antioxidants such as ascorbic acid.

本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical composition of the present invention can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers can be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. Emulsions can also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs prepared with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose can be used. Such preparations can also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。The pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution. Acceptable vehicles and solvents that may be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol and processed to form a microemulsion. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, the solution and microemulsion may be preferably administered in a manner that maintains a constant circulating concentration of the compound of the present invention. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used.

本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如在1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。The pharmaceutical composition of the present invention can be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared according to known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. The sterile injection preparation can also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, such as a solution prepared in 1,3-butanediol. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be used to prepare injections.

可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。The compounds of the invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and which will dissolve in the rectum to release the drug. Such materials include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.

本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。It is well known to those skilled in the art that the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the patient's age, the patient's weight, the patient's health condition, the patient's behavior, the patient's diet, the administration time, the administration method, the excretion rate, the combination of drugs, etc. In addition, the best treatment method such as the mode of treatment, the daily dosage of the general compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.

本发明可以含有通式化合物及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活性成分，也可以与其它治疗药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。 The present invention can contain the general formula compound and its pharmaceutically acceptable salt, hydrate or solvate as active ingredient, mixed with pharmaceutically acceptable carrier or excipient to prepare a composition, and prepared into a clinically acceptable dosage form. The derivative of the present invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions, etc. The compound of the present invention can be used as the only active ingredient, or it can be used in combination with other therapeutic drugs. Combined therapy is achieved by administering each therapeutic component simultaneously, separately or successively.

术语说明Terminology

除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated otherwise, the terms used in the specification and claims have the following meanings.

本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，即本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素包括19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。The carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds described in the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.

术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基、含有1至4个碳原子的烷基或含有1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基可以为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, an alkyl group containing 1 to 4 carbon atoms or an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, and the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

术语“亚烷基”指二价烷基，其中烷基如上所定义，其具有1至20个(例如1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19或20个)碳原子(即C1-20亚烷基)。所述亚烷基优选具有1至12个碳原子的亚烷基(即C1-12亚烷基)，更优选含有1至6个碳原子的亚烷基(即C1-6亚烷基)，进一步优选 含有1至4个碳原子的亚烷基(即C1-6亚烷基)。亚烷基的非限制性实例包括但不限于亚甲基(-CH2-)、1,1-亚乙基(-CH(CH3)-)、1,2-亚乙基(-CH2CH2-)、1,1-亚丙基(-CH(CH2CH3)-)、1,2-亚丙基(-CH2CH(CH3)-)、1,3-亚丙基(-CH2CH2CH2-)和1,4-亚丁基(-CH2CH2CH2CH2-)等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，取代基可以选自烷基、烯基、炔基、烷氧基、卤代烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个。The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group is as defined above, and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., C 1-20 alkylene). The alkylene group is preferably an alkylene group having 1 to 12 carbon atoms (i.e., C 1-12 alkylene), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C 1-6 alkylene), and further preferably An alkylene group having 1 to 4 carbon atoms (i.e., C 1-6 alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene (—CH 2 —), 1,1-ethylene (—CH(CH 3 )—), 1,2-ethylene (—CH 2 CH 2 —), 1,1-propylene (—CH(CH 2 CH 3 )—), 1,2-propylene (—CH 2 CH(CH 3 )—), 1,3-propylene (—CH 2 CH 2 CH 2 —), and 1,4-butylene (—CH 2 CH 2 CH 2 CH 2 —), and the like. The alkylene group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituents may be selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的一价烃基，优选含有2至4个碳原子的烯基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基可以为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkenyl" refers to a monovalent hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably an alkenyl group containing 2 to 4 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的一价烃基，优选含有2至4个碳原子的炔基或优选含有3至4个碳原子的炔基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基可以为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkynyl" refers to a monovalent hydrocarbon group consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably an alkynyl group containing 2 to 4 carbon atoms or preferably an alkynyl group containing 3 to 4 carbon atoms, such as ethynyl, propynyl, butynyl, etc. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.

术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14, more preferably 7 to 10. According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is a 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但 没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but None of the rings has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of condensed cycloalkyl include:

术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基可以为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含4至12个环原子，其中1～4个是杂原子；更优选包含7至12个环原子，其中1～4个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 4 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 7 to 12 ring atoms, of which 1 to 4 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl. The polycyclic heterocyclic group includes spiro, fused and bridged heterocyclic groups.

术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至12元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或 5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called spiro atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 12 members. According to the number of spiro atoms shared between rings, spiroheterocyclic groups are divided into monospiroheterocyclic groups, bispiroheterocyclic groups or polyspiroheterocyclic groups, preferably monospiroheterocyclic groups and bispiroheterocyclic groups. More preferably, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 6-membered 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至12元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 12 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至12元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 12 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括： The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

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杂环基可以是任选取代的或非取代的，当被取代时，取代基可以为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

芳基可以是取代的或非取代的，当被取代时，取代基可以为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The aryl group may be substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidyl, thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

杂芳基可以是任选取代的或非取代的，当被取代时，取代基可以为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基可以为一 个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent may be one or more of the following: one or more of the following groups are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

上述烯基、炔基、环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同环原子或两个不同的环原子上除去两个氢原子所衍生的残基即“亚烯基”、“亚炔基”、“亚环烷基”、“亚杂环基”、“亚芳基”和“亚杂芳基”。The alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups mentioned above include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same ring atom or two different ring atoms of the parent by removing two hydrogen atoms, namely, "alkenylene", "alkynylene", "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

术语“环烷氧基”指-O-(环烷基)，其中环烷基如上所定义。The term "cycloalkoxy" refers to an -O-(cycloalkyl) group, wherein cycloalkyl is as defined above.

术语“杂环烷氧基”指-O-(杂环基)，其中杂环基如上所定义。The term "heterocycloalkoxy" refers to -O-(heterocyclyl) wherein heterocyclyl is as defined above.

术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

术语“羟基”指-OH。The term "hydroxy" refers to -OH.

术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.

术语“氨基”指-NH2。The term "amino" refers to -NH2 .

术语“氰基”指-CN。The term "cyano" refers to -CN.

术语“硝基”指-NO2。The term "nitro" refers to -NO2 .

术语“氧代基”指＝O。The term "oxo" refers to =0.

术语“硫代基”指＝S。The term "thio" refers to =S.

术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.

术语“巯基”指-SH。The term "thiol" refers to -SH.

术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。The term "ester group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

术语“酰基”指-C(O)R基团的化合物，其中R为烷基、环烷基、杂环基、芳基、杂芳基。The term "acyl" refers to a compound of the group -C(O)R, wherein R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.

“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的 盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。A "pharmaceutical composition" is a composition containing one or more of the compounds described herein or a physiologically/pharmaceutically acceptable A mixture of a salt or prodrug with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

“可药用盐”或“药学上可接受的盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity.

“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。"Carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

具体实施方式Detailed ways

进一步通过实施例来理解本发明的化合物及其制备，这些实施例说明了一些制备或使用所述化合物的方法。然而，要理解的是，这些实施例不限制本发明。现在已知的或进一步开发的本发明的变化被认为落入本文中描述的和要求保护的本发明范围之内。The compounds of the present invention and their preparation are further understood by way of examples, which illustrate some methods of preparing or using the compounds. However, it is to be understood that these examples do not limit the present invention. Variations of the present invention now known or further developed are considered to fall within the scope of the invention described herein and claimed.

本发明化合物是利用便利的起始原料和通用的制备步骤来完成制备的。本发明给出了典型的或倾向性的反应条件，诸如反应温度、时间、溶剂、压力、反应物的摩尔比。但是除非特殊说明，其他反应条件也能采纳。优化条件可能随着具体的反应物或溶剂的使用而改变，但在通常情况下，反应优化步骤和条件都能得到确定。The compounds of the present invention are prepared using convenient starting materials and common preparation steps. The present invention provides typical or preferred reaction conditions, such as reaction temperature, time, solvent, pressure, and molar ratio of reactants. However, unless otherwise specified, other reaction conditions can also be adopted. The optimized conditions may change with the use of specific reactants or solvents, but in general, the reaction optimized steps and conditions can be determined.

另外，本发明中可能用到了一些保护基团来保护某些官能团避免不必要的反应。适宜于各种官能团的保护基以及它们的保护或脱保护条件已经为本领域技术人员广泛熟知。例如T.W.Greene和G.M.Wuts的《有机制备中的保护基团》(第3版,Wiley,New York,1999和书中的引用文献)详细描述了大量的保护基团的保护或脱保护。In addition, some protecting groups may be used in the present invention to protect certain functional groups from unwanted reactions. Protecting groups suitable for various functional groups and their protection or deprotection conditions are widely known to those skilled in the art. For example, T. W. Greene and G. M. Wuts's "Protective Groups in Organic Preparations" (3rd edition, Wiley, New York, 1999 and references therein) describes in detail the protection or deprotection of a large number of protecting groups.

化合物和中间体的分离和纯化依据具体的需求采取适当的方法和步骤，例如过滤、萃取、蒸馏、结晶、柱层析、制备薄层板色谱、制备高效液相色谱或上述方法的混合使用。其具体使用方法可参阅本发明描述的实例。当然，其他类似的分离和纯化手段也是可以采用的。可以使用常规方法(包括物理常数和波谱数据)对其进行表征。The separation and purification of compounds and intermediates can be carried out by appropriate methods and steps according to specific needs, such as filtration, extraction, distillation, crystallization, column chromatography, preparative thin layer plate chromatography, preparative high performance liquid chromatography or a combination of the above methods. The specific use method can refer to the examples described in the present invention. Of course, other similar separation and purification means can also be adopted. Conventional methods (including physical constants and spectral data) can be used to characterize them.

化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10-6(ppm)的单位给出。NMR的测定是用WNMR-I-400MHz型核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts are given in units of 10 -6 (ppm). NMR measurements are performed using a WNMR-I-400MHz nuclear magnetic spectrometer, with deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

MS的测定用LC(Agilent 1260 Infinity)/MS(G6125B)质谱仪(生产商：安捷伦)。MS was determined using LC (Agilent 1260 Infinity)/MS (G6125B) mass spectrometer (manufacturer: Agilent).

制备液相色谱法使用GX-281高效液相色谱仪(生产商：GILSON)。色谱柱为5μm EVO C18 100(100mm×30.0mm)，流动相：乙腈/水。 The preparative liquid chromatography method used a GX-281 high performance liquid chromatograph (manufacturer: GILSON). The chromatographic column was 5μm EVO C18 100 (100mm×30.0mm), mobile phase: acetonitrile/water.

薄层色谱法(TLC)使用青岛海洋化工GF254硅胶板，反应监测用薄层色谱法使用的硅胶板采用的规格是0.20mm～0.25mm，分离纯化用薄层色谱法使用的硅胶板采用的规格是0.5mm。Thin layer chromatography (TLC) used Qingdao Ocean Chemical GF254 silica gel plate. The silica gel plate used in reaction monitoring thin layer chromatography adopted a specification of 0.20 mm to 0.25 mm, and the silica gel plate used in separation and purification thin layer chromatography adopted a specification of 0.5 mm.

硅胶柱层析色谱法使用青岛海洋硅胶100～200目、200～300目和300～400目硅胶为载体。Silica gel column chromatography uses Qingdao marine silica gel 100-200 mesh, 200-300 mesh and 300-400 mesh silica gel as the carrier.

本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、北京偶合、Sigma、百灵威、易世明、上海书亚、上海伊诺凯、安耐吉化学、上海毕得、南京药石等公司。The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from online shopping malls, Beijing Coupling, Sigma, Bailingwei, Yishiming, Shanghai Shuya, Shanghai Inokai, Anaiji Chemical, Shanghai Bid, Nanjing Yaoshi and other companies.

实施例中无特殊说明，反应能够均在氮气氛下进行。Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

反应溶剂、有机溶剂或惰性溶剂各自表述为使用的该溶剂在所描述的反应条件下不参与反应，包括，如苯、甲苯、乙腈、四氢呋喃(THF)、二甲基甲酰胺(DMF)、氯仿、二氯甲烷、乙醚、甲醇、氮-甲基吡咯碄酮(NMP)、吡啶等。实施例中无特殊说明，溶液是指水溶液。Reaction solvent, organic solvent or inert solvent are each expressed as the solvent used that does not participate in the reaction under the described reaction conditions, including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, dichloromethane, ether, methanol, nitrogen-methylpyrrolidone (NMP), pyridine, etc. Unless otherwise specified in the examples, the solution refers to an aqueous solution.

本发明中所描述的化学反应一般在常压下进行。反应时间和条件为，例如，一个大气压下，-78℃至200℃之间，大约1至24小时内完成。如果反应过夜，则反应时间一般为16小时。实施例中无特殊说明，反应的温度为室温，为20℃～30℃。The chemical reactions described in the present invention are generally carried out under normal pressure. The reaction time and conditions are, for example, between -78°C and 200°C at one atmosphere, and completed within about 1 to 24 hours. If the reaction is overnight, the reaction time is generally 16 hours. Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，C：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。The reaction progress in the examples was monitored by thin layer chromatography (TLC), and the developing solvent systems used in the reaction were: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system, C: acetone, and the volume ratio of the solvents was adjusted according to the polarity of the compounds.

纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和三氟乙酸等碱性或酸性试剂进行调节。The eluent system of column chromatography and the developing solvent system of thin layer chromatography used for purifying compounds include: A: dichloromethane and methanol system, B: petroleum ether and ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and trifluoroacetic acid can also be added for adjustment.

除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any method and material similar or equivalent to the described content can be applied to the method of the present invention.

制备例1：4-溴-3-氟-5-硝基吡啶(中间体A1)的合成
Preparation Example 1: Synthesis of 4-bromo-3-fluoro-5-nitropyridine (Intermediate A1)

步骤1：3-氟-5-硝基吡啶-4-胺(A1-2)的制备Step 1: Preparation of 3-fluoro-5-nitropyridine-4-amine (A1-2)

3-氟吡啶-4-胺(A1-1)(30g,268mmol,1.0eq.)溶解在冷的浓硫酸(180mL)中，在冰浴下滴加浓HNO3(42.2g,402mmol,1.5eq.)，并升温至60℃搅拌3小时。反应 液降至室温，反应混合物加至1000mL冰水中，再加入400mL KOH水溶液(10mol/L)至pH＝12，再加入500mL乙酸乙酯，乙酸乙酯萃取三次，合并有机相，并用500mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物通过快速柱色谱法(洗脱剂：石油醚/乙酸乙酯＝1：2)纯化，得到黄色固体状的化合物A1-2，15.0g，收率33.8％。3-Fluoropyridin-4-amine (A1-1) (30 g, 268 mmol, 1.0 eq.) was dissolved in cold concentrated sulfuric acid (180 mL), concentrated HNO 3 (42.2 g, 402 mmol, 1.5 eq.) was added dropwise under an ice bath, and the temperature was raised to 60° C. and stirred for 3 hours. The mixture was cooled to room temperature, the reaction mixture was added to 1000 mL of ice water, and then 400 mL of KOH aqueous solution (10 mol/L) was added to pH = 12, and then 500 mL of ethyl acetate was added, and the mixture was extracted with ethyl acetate three times. The organic phases were combined and washed with 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate = 1:2) to obtain compound A1-2 as a yellow solid, 15.0 g, with a yield of 33.8%.

步骤2：4-溴-3-氟-5-硝基吡啶(A1)的制备Step 2: Preparation of 4-bromo-3-fluoro-5-nitropyridine (A1)

将化合物A1-2(15g,98.5mmol,1.0eq.)溶解在无水ACN(150mL)中，再加入CuBr(21.5g,150mmol,1.5eq.)，70℃搅拌下滴加亚硝酸叔丁酯(16g,150mmol,1.5eq.)，70℃搅拌4小时。反应混合物加水300mL，再加入300mL乙酸乙酯，乙酸乙酯萃取3次，合并有机相，并用300mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物通过快速柱色谱法(洗脱剂：石油醚/乙酸乙酯＝5：2)纯化，得到黄色固体状的化合物A1，7.0g，收率85.7％。Compound A1-2 (15 g, 98.5 mmol, 1.0 eq.) was dissolved in anhydrous ACN (150 mL), and CuBr (21.5 g, 150 mmol, 1.5 eq.) was added. Tert-butyl nitrite (16 g, 150 mmol, 1.5 eq.) was added dropwise at 70°C with stirring, and stirred at 70°C for 4 hours. 300 mL of water was added to the reaction mixture, and 300 mL of ethyl acetate was added. The mixture was extracted with ethyl acetate for 3 times, and the organic phases were combined and washed with 300 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate = 5:2) to obtain compound A1 as a yellow solid, 7.0 g, with a yield of 85.7%.

制备例2：3-氨基-6-(4-(异丙基磺酰基)苯基)吡嗪-2-羧酸(中间体A2)的合成
Preparation Example 2: Synthesis of 3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxylic acid (Intermediate A2)

步骤1：3-氨基-6-(4-(异丙基磺酰基)苯基)吡嗪-2-羧酸甲酯(A2-3)的制备Step 1: Preparation of methyl 3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxylate (A2-3)

将3-氨基-6-溴吡嗪-2-羧酸甲酯(A2-1)(10.0g,43.3mmol,1.0eq.)、(4-(异丙基磺酰基)苯基)硼酸(A2-2)(11.9g,52mmol,1.2eq.)、Cs2CO3(42.4g,130mmol,3.0eq.)、Pd(dppf)Cl2(800mg,8％)溶解在二氧六环(90mL)中，再加入10mL水。氮气氛下，80℃搅拌8小时。反应混合物加水300mL，再加入300mL乙酸乙酯洗涤，乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法纯化，得到黄色固体状的化合物A2-3，11.0g，收率75.8％。3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (A2-1) (10.0 g, 43.3 mmol, 1.0 eq.), (4-(isopropylsulfonyl)phenyl)boric acid (A2-2) (11.9 g, 52 mmol, 1.2 eq.), Cs2CO3 (42.4 g, 130 mmol, 3.0 eq.), Pd(dppf)Cl 2 (800 mg, 8%) were dissolved in dioxane (90 mL), and 10 mL of water was added. The mixture was stirred at 80°C for 8 hours under a nitrogen atmosphere. 300 mL of water was added to the reaction mixture, and 300 mL of ethyl acetate was added for washing. The mixture was extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound A2-3 as a yellow solid, 11.0 g, with a yield of 75.8%.

步骤2：3-氨基-6-(4-(异丙基磺酰基)苯基)吡嗪-2-羧酸(A2)的制备Step 2: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxylic acid (A2)

将化合物A2-3(11g,32.8mmol,1.0eq.)溶解在MeOH/THF/H2O(3：2：1，100mL)中，再加入LiOH.H2O(4.2g,98.4mmol,3.0eq.)，25℃搅拌8小时。反应混合物滴加1moL/L HCl，至反应液固体不再析出，将得到的固体过滤，得到黄色固体状的化合物A2，7.4g，收率74.0％。Compound A2-3 (11 g, 32.8 mmol, 1.0 eq.) was dissolved in MeOH/THF/H 2 O (3:2:1, 100 mL), and LiOH.H 2 O (4.2 g, 98.4 mmol, 3.0 eq.) was added, and stirred at 25°C for 8 hours. 1 mol/L HCl was added dropwise to the reaction mixture until no solid precipitated from the reaction solution, and the obtained solid was filtered to obtain compound A2 as a yellow solid, 7.4 g, with a yield of 74.0%.

制备例3：1-(3-(3-氨基-6-(4-(异丙基磺酰基)苯基)吡嗪-2-甲酰胺基)-5-氟吡啶-4-基)哌啶-4-羧酸(中间体A3)的合成
Preparation Example 3: Synthesis of 1-(3-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid (Intermediate A3)

步骤1：1-(3-氟-5-硝基吡啶-4-基)哌啶-4-羧酸甲酯(A3-2)的制备Step 1: Preparation of methyl 1-(3-fluoro-5-nitropyridin-4-yl)piperidine-4-carboxylate (A3-2)

将化合物A1(3.1g,14.1mmol,1.0eq.)、哌啶-4-羧酸甲酯(A3-1)(2.44g,17mmol,1.2eq.)、TEA(2.9g,28.2mmol,2.0eq.)溶解在DMF(20mL)中，25℃搅拌3小时。反应混合物加水100mL，再加入100mL乙酸乙酯萃取，乙酸乙酯萃取3次，合并有机相，并用100mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物通过快速柱色谱法(洗脱剂：石油醚/乙酸乙酯＝1：1)纯化，得到黄色固体状的化合物A3-2，3.4g，收率82.5％。Compound A1 (3.1 g, 14.1 mmol, 1.0 eq.), piperidine-4-carboxylic acid methyl ester (A3-1) (2.44 g, 17 mmol, 1.2 eq.), TEA (2.9 g, 28.2 mmol, 2.0 eq.) were dissolved in DMF (20 mL) and stirred at 25°C for 3 hours. 100 mL of water was added to the reaction mixture, and 100 mL of ethyl acetate was added for extraction. The ethyl acetate was extracted 3 times, and the organic phases were combined and washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent: petroleum ether/ethyl acetate = 1:1) to obtain compound A3-2 as a yellow solid, 3.4 g, with a yield of 82.5%.

步骤2：1-(3-氟-5-硝基吡啶-4-基)哌啶-4-羧酸甲酯(A3-3)的制备Step 2: Preparation of methyl 1-(3-fluoro-5-nitropyridin-4-yl)piperidine-4-carboxylate (A3-3)

将化合物A3-2(3.4g,12mmol,1.0eq.)溶解在无水甲醇(40mL)中，再加入Pd/C(680mg,20％)，氢气氛下，25℃搅拌16小时。反应混合物经硅藻土过滤后，甲醇洗涤滤饼，滤液减压浓缩，得到黄色固体状的化合物A3-3，3.0g，收率96.5％。Compound A3-2 (3.4 g, 12 mmol, 1.0 eq.) was dissolved in anhydrous methanol (40 mL), and Pd/C (680 mg, 20%) was added, and stirred at 25°C for 16 hours under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain compound A3-3 as a yellow solid, 3.0 g, with a yield of 96.5%.

步骤3：1-(3-(3-氨基-6-(4-(异丙基磺酰基)苯基)吡嗪-2-甲酰胺基)-5-氟吡啶-4-基)哌啶-4-羧酸甲酯(A3-4)的制备Step 3: Preparation of methyl 1-(3-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylate (A3-4)

将化合物A2(4.3g,13.4mmol,1.0eq.)、化合物A3-3(4.1g,16.1mmol,1.2eq.)、DIEA(4.2g,32.2mmol,2.5eq.)、HATU(6.6g,17.4mmol,1.3eq.)溶解在DMF(30mL)中，25℃搅拌3小时。反应混合物加水30mL，搅拌8分钟，再加入10mL水继续搅拌5分钟。固体析出，反应混合物过滤，滤饼用8mL甲醇洗涤，再用8mL乙酸乙酯洗涤。滤饼干燥，得到黄色固体状的化合物A3-4，4.9g，收率66.2％。Compound A2 (4.3 g, 13.4 mmol, 1.0 eq.), compound A3-3 (4.1 g, 16.1 mmol, 1.2 eq.), DIEA (4.2 g, 32.2 mmol, 2.5 eq.), and HATU (6.6 g, 17.4 mmol, 1.3 eq.) were dissolved in DMF (30 mL) and stirred at 25 °C for 3 hours. 30 mL of water was added to the reaction mixture, stirred for 8 minutes, and then 10 mL of water was added and stirred for 5 minutes. Solid precipitated, the reaction mixture was filtered, and the filter cake was washed with 8 mL of methanol and then with 8 mL of ethyl acetate. The filter cake was dried to obtain compound A3-4 as a yellow solid, 4.9 g, with a yield of 66.2%.

步骤4：1-(3-(3-氨基-6-(4-(异丙基磺酰基)苯基)吡嗪-2-甲酰胺基)-5-氟吡啶-4-基)哌啶-4-羧酸(A3)的制备Step 4: Preparation of 1-(3-(3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamido)-5-fluoropyridin-4-yl)piperidine-4-carboxylic acid (A3)

将化合物A3-4(4.9g,8.8mmol,1.0eq.)溶解在MeOH/DCM/H2O(3：2：1，50mL)中，再加入LiOH.H2O(11.1g,26.4mmol,3.0eq.)，40℃搅拌6小时。反应混合物滴加1moL/L HCl，至反应液固体不再析出，过滤，得到黄色固体状的化合物A3，4.1g，收率84.3％。 Compound A3-4 (4.9 g, 8.8 mmol, 1.0 eq.) was dissolved in MeOH/DCM/H 2 O (3:2:1, 50 mL), and LiOH.H 2 O (11.1 g, 26.4 mmol, 3.0 eq.) was added, and stirred at 40°C for 6 hours. 1 mol/L HCl was added dropwise to the reaction mixture until no solid precipitated from the reaction solution, and the mixture was filtered to obtain compound A3 as a yellow solid, 4.1 g, with a yield of 84.3%.

实施例1：3-氨基-6-(4-(甲磺酰基)苯基)-N-(1H-吡咯并[2,3-b]吡啶-4-基)吡唑-2-甲酰胺(1)的制备
Example 1: Preparation of 3-amino-6-(4-(methylsulfonyl)phenyl)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrazole-2-carboxamide (1)

步骤1：3-氨基-6-(4-(甲基磺酰基)苯基)吡嗪-2-羧酸甲酯(1-3)的制备Step 1: Preparation of methyl 3-amino-6-(4-(methylsulfonyl)phenyl)pyrazine-2-carboxylate (1-3)

3-氨基-6-溴吡嗪-2-羧酸甲酯(1-1)(500mg,2.16mmol,1.00eq)、(4-(甲基磺酰基)苯基)硼酸(1-2)(476mg,2.38mmol,1.1eq)、1,1'-双二苯基膦二茂铁二氯化钯(354mg,0.43mmol,0.2eq)、碳酸钠(459mg,4.3mmol,2.00eq)溶于二氧六环(10mL)和水(1mL)中，氮气氛下，100℃反应1.5小时。然后，将反应液真空浓缩得粗品，粗品经柱层析色谱法(洗脱剂：100％乙酸乙酯/石油醚)纯化，得黑色固体状的化合物1-3(544mg，收率84％，纯度93％)。3-Amino-6-bromopyrazine-2-carboxylic acid methyl ester (1-1) (500 mg, 2.16 mmol, 1.00 eq), (4-(methylsulfonyl)phenyl)boric acid (1-2) (476 mg, 2.38 mmol, 1.1 eq), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (354 mg, 0.43 mmol, 0.2 eq), sodium carbonate (459 mg, 4.3 mmol, 2.00 eq) were dissolved in dioxane (10 mL) and water (1 mL), and reacted at 100 ° C for 1.5 hours under nitrogen atmosphere. Then, the reaction solution was concentrated in vacuo to obtain a crude product, which was purified by column chromatography (eluent: 100% ethyl acetate/petroleum ether) to obtain compound 1-3 as a black solid (544 mg, yield 84%, purity 93%).

LCMS(ESI)m/z 308,(M+H)+。LCMS (ESI) m/z 308, (M+H) + .

步骤2：3-氨基-6-(4-(甲基磺酰基)苯基)吡嗪-2-羧酸(1-4)的制备Step 2: Preparation of 3-amino-6-(4-(methylsulfonyl)phenyl)pyrazine-2-carboxylic acid (1-4)

将化合物1-3(544mg,1.77mmol,1.0eq.)、氢氧化锂(212mg,8.85mmol,5.0eq.)溶于甲醇(5mL)和水(5mL)中，升温至90℃反应2小时。反应混合物冷却，加入1N稀盐酸，有固体析出，过滤得滤饼，真空浓缩，得粗品化合物1-4，黑色固体(375mg,收率72％，纯度95％)。Compound 1-3 (544 mg, 1.77 mmol, 1.0 eq.) and lithium hydroxide (212 mg, 8.85 mmol, 5.0 eq.) were dissolved in methanol (5 mL) and water (5 mL), and the temperature was raised to 90°C for 2 hours. The reaction mixture was cooled, and 1N dilute hydrochloric acid was added to precipitate solids, which were filtered to obtain a filter cake, and vacuum concentrated to obtain a crude compound 1-4 as a black solid (375 mg, yield 72%, purity 95%).

LCMS(ESI)m/z 294,(M+H)+。LCMS (ESI) m/z 294, (M+H) + .

步骤3：3-氨基-6-(4-(甲磺酰基)苯基)-N-(1H-吡咯并[2,3-b]吡啶-4-基)吡唑-2-甲酰胺(1)的制备Step 3: Preparation of 3-amino-6-(4-(methylsulfonyl)phenyl)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrazole-2-carboxamide (1)

将化合物1-4(100mg,0.34mmol,1.00eq)、1H-吡咯并[2,3-b]吡啶-4-胺(1-5)(45mg,0.34mmol,1.0eq)、HATU(156mg,0.42mmol,1.2eq)、DIPEA(132mg,1.02mmol,3.00eq)溶于DMF(3mL)中，在室温反应2小时。将反应液通过反相制备高效液相色谱法(流动相为水/乙腈＝100％-70％/30％，梯度淋洗，流动相中按体积百分比添加0.1％甲酸，流速为20.0mL/min)纯化，得化合物1，黄色固体(30.5mg，收率22％，纯度98％)。Compound 1-4 (100 mg, 0.34 mmol, 1.00 eq), 1H-pyrrolo[2,3-b]pyridin-4-amine (1-5) (45 mg, 0.34 mmol, 1.0 eq), HATU (156 mg, 0.42 mmol, 1.2 eq), and DIPEA (132 mg, 1.02 mmol, 3.00 eq) were dissolved in DMF (3 mL) and reacted at room temperature for 2 hours. The reaction solution was purified by reverse phase preparative high performance liquid chromatography (mobile phase was water/acetonitrile = 100%-70%/30%, gradient elution, 0.1% formic acid was added to the mobile phase by volume percentage, and the flow rate was 20.0 mL/min) to obtain compound 1 as a yellow solid (30.5 mg, yield 22%, purity 98%).

LCMS(ESI)m/z 409,(M+H)+。 LCMS (ESI) m/z 409, (M+H) + .

1H NMR(400MHz,DMSO-d6)δ11.2(s,1H),10.55(s,1H),9.03(s,1H),8.51(d,J＝8.5Hz,2H),8.33(s,1H),7.97–7.82(m,4H),7.63(d,J＝8.4Hz,1H),6.95(d,J＝8.7Hz,1H),3.23(s,3H)。 1 H NMR (400 MHz, DMSO-d6) δ 11.2 (s, 1H), 10.55 (s, 1H), 9.03 (s, 1H), 8.51 (d, J = 8.5 Hz, 2H), 8.33 (s, 1H), 7.97–7.82 (m, 4H), 7.63 (d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.7 Hz, 1H), 3.23 (s, 3H).

实施例2：3-氨基-6-(4-(异丙基磺酰基)苯基)-N-(4-((甲氨基)甲基)苄基)吡唑-2-甲酰胺(2)的制备
Example 2: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-(4-((methylamino)methyl)benzyl)pyrazole-2-carboxamide (2)

步骤1：(4-((3-氨基-6-(4-(异丙基磺酰基)苯基)吡嗪-2-甲酰胺基)甲基)苄基)(甲基)氨基甲酸叔丁酯(2-2)的制备Step 1: Preparation of tert-butyl (4-((3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazine-2-carboxamido)methyl)benzyl)(methyl)carbamate (2-2)

向化合物A2(500mg,1.5mmol,1.0eq.)、HATU(709.9mg,1.87mmol,1.2eq.)、DIPEA(401mg,3.1mmol,2.0eq.)的DMF(6ml)溶液中加入(4-(氨基甲基)苄基)(甲基)氨基甲酸叔丁酯(2-1)(467mg,1.87mmol,1.2eq.)，在室温搅拌1小时。反应混合物用水(30ml)淬灭，乙酸乙酯萃取，饱和NaHCO3洗涤，饱和食盐水洗涤，减压浓缩得，无色透明液体化合物2-2(800mg，收率92％，纯度95％)。To a DMF (6 ml) solution of compound A2 (500 mg, 1.5 mmol, 1.0 eq.), HATU (709.9 mg, 1.87 mmol, 1.2 eq.), DIPEA (401 mg, 3.1 mmol, 2.0 eq.), tert-butyl (4-(aminomethyl)benzyl)(methyl)carbamate (2-1) (467 mg, 1.87 mmol, 1.2 eq.) was added, and stirred at room temperature for 1 hour. The reaction mixture was quenched with water (30 ml), extracted with ethyl acetate, washed with saturated NaHCO 3 , washed with saturated brine, and concentrated under reduced pressure to obtain a colorless transparent liquid compound 2-2 (800 mg, yield 92%, purity 95%).

LCMS(ESI)m/z 554.69,(M+H)+。LCMS (ESI) m/z 554.69, (M+H) + .

步骤2：3-氨基-6-(4-(异丙基磺酰基)苯基)-N-(4-((甲氨基)甲基)苄基)吡唑-2-甲酰胺(2)的制备Step 2: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-(4-((methylamino)methyl)benzyl)pyrazole-2-carboxamide (2)

向化合物2-2(800mg,1.44mmol,1.0eq.)的DCM(10ml)溶液中加入TFA(2ml)，在室温搅拌0.5小时。反应混合物用1mol/L的NaOH/H2O溶液调PH值至10-11，DCM萃取，饱和食盐水洗涤，减压浓缩，残余物用快速硅胶柱色谱法纯化(洗脱剂：MeOH/DCM＝0％～10％)，得黄色固体状化合物2(390mg，收率59％，纯度96％)。TFA (2 ml) was added to a DCM (10 ml) solution of compound 2-2 (800 mg, 1.44 mmol, 1.0 eq.), and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was adjusted to pH 10-11 with 1 mol/L NaOH/H 2 O solution, extracted with DCM, washed with saturated brine, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluent: MeOH/DCM=0%-10%) to obtain yellow solid compound 2 (390 mg, yield 59%, purity 96%).

LCMS(ESI)m/z 454,(M+H)+。LCMS (ESI) m/z 454, (M+H) + .

1H NMR(400MHz,DMSO)δ9.49(s,1H),8.99(s,1H),8.48(d,J＝8.4Hz,2H),7.89(d,J＝8.4Hz,4H),7.28(q,J＝8.4Hz,4H),4.53(d,J＝6.4Hz,2H),3.61(s,2H),3.46(dt,J＝13.2,6.6Hz,2H),2.24(s,3H),1.18(d,J＝6.8Hz,6H)。)。 1 H NMR (400 MHz, DMSO) δ9.49 (s, 1H), 8.99 (s, 1H), 8.48 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.4 Hz, 4H), 7.28 ( q, J = 8.4 Hz, 4H), 4.53 (d, J = 6.4 Hz, 2H), 3.61 (s, 2H), 3.46 (dt, J = 13.2, 6.6 Hz, 2H), 2.24 (s, 3H), 1.18 (d, J = 6.8 Hz, 6H). ).

参照实施例2的合成方法制备以下化合物：
The following compounds were prepared by the synthetic method of Example 2:

实施例3：(3-氨基-6-(4-(异丙基磺酰基)苯基)吡嗪-2-基)(3,4-二氢异喹啉-2(1H)-基)甲酮(3)的制备

Example 3: Preparation of (3-amino-6-(4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)(3,4-dihydroisoquinolin-2(1H)-yl)methanone (3)

将化合物A2(50mg,155.6mmol,1.0eq.)、1,2,3,4-四氢异喹啉(3-1)(27mg,203mmol,1.3eq.)、HATU(77mg,203mmol,1.0eq.)、DIPEA(41mg,318mmol,2.0eq.)溶解在DMF(2mL)中，25℃搅拌14小时。反应混合物加水2mL搅拌10分钟，再加入6mL水继续搅拌10分钟，混合物过滤，滤饼用2mL甲醇淋洗，再用2mL乙酸乙酯淋洗，收集滤饼，并干燥，得到黄色固体状化合物3，63mg(收率92.6％，纯度96.2％)。Compound A2 (50 mg, 155.6 mmol, 1.0 eq.), 1,2,3,4-tetrahydroisoquinoline (3-1) (27 mg, 203 mmol, 1.3 eq.), HATU (77 mg, 203 mmol, 1.0 eq.), and DIPEA (41 mg, 318 mmol, 2.0 eq.) were dissolved in DMF (2 mL) and stirred at 25°C for 14 hours. 2 mL of water was added to the reaction mixture and stirred for 10 minutes, and then 6 mL of water was added and stirred for 10 minutes. The mixture was filtered, and the filter cake was rinsed with 2 mL of methanol and then with 2 mL of ethyl acetate. The filter cake was collected and dried to obtain 63 mg of compound 3 as a yellow solid (yield 92.6%, purity 96.2%).

LCMS(ESI)m/z 437,(M+H)+。LCMS (ESI) m/z 437, (M+H) + .

1H NMR(400MHz,DMSO)δ8.85(s,1H),8.22(d,J＝8.4Hz,2H),7.90(d,J＝8.8Hz,2H),7.25(d,J＝28.6Hz,3H),6.98(s,2H),4.84(s,1H),4.75(s,1H),3.91(s,1H),3.71(s,1H),3.44(s,1H),2.91(d,J＝12.0Hz,2H),2.08–1.93(m,1H),1.18(d,J＝6.8Hz,6H)。 1 H NMR (400 MHz, DMSO) δ8.85 (s, 1H), 8.22 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 28.6 Hz, 3H), 6.98 (s, 2H), 4.84 (s, 1H), 4.75 (s, 1H), 3.91 (s, 1H), 3.71 (s, 1H), 3.44 (s, 1H), 2.91 (d, J = 12.0 Hz, 2H), 2.08–1.93 (m, 1H), 1.18 (d, J = 6.8 Hz, 6H).

参照实施例3的合成方法制备以下化合物：

The following compounds were prepared by the synthetic method of Example 3:

实施例5：3-氨基-6-(4-(异丙基磺酰基)苯基)-N-(4-((甲氨基)甲基)苯甲酰基)吡唑-2-甲酰胺(5)的制备

Example 5: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-(4-((methylamino)methyl)benzoyl)pyrazole-2-carboxamide (5)

向H5IO6(602.9mg,2.64mmol,6.0eq.)、CrO3(2.2mg,0.02mmol,5mol％)的ACN(6ml)溶液中加入Ac2O(270mg,2.64mmol,6.0eq.)，在0℃搅拌0.5小时。再向反应混合物中加化合物2(200mg,0.44mmol,1.0eq.)。反应混合物用水(30ml)淬灭，乙酸乙酯萃取，饱和NaHCO3洗涤，饱和食盐水洗涤，减压浓缩，残余物通过快速硅胶柱层析色谱法(洗脱剂：MeOH/DCM＝0％～10％)纯化，得黄色固体化合物5(3mg,收率1.5％，纯度96％)。Ac 2 O (270 mg, 2.64 mmol, 6.0 eq.) was added to a solution of H 5 IO 6 (602.9 mg, 2.64 mmol, 6.0 eq.) and CrO 3 (2.2 mg, 0.02 mmol, 5 mol%) in ACN (6 ml), and the mixture was stirred at 0°C for 0.5 h. Compound 2 (200 mg, 0.44 mmol, 1.0 eq.) was then added to the reaction mixture. The reaction mixture was quenched with water (30 ml), extracted with ethyl acetate, washed with saturated NaHCO 3 , washed with saturated brine, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (eluent: MeOH/DCM=0%-10%) to obtain yellow solid compound 5 (3 mg, yield 1.5%, purity 96%).

LCMS(ESI)m/z 468,(M+H)+。LCMS (ESI) m/z 468, (M+H) + .

1H NMR(400MHz,DMSO)δ9.13(s,1H),8.41(d,J＝8.4Hz,2H),7.98(d，J＝8.0Hz 1H)，7.92(d，J＝7.8Hz 1H),7.63(d,J＝8.0Hz,2H),4.36(s,1H),3.93(s,2H),3.53–3.45(m,1H),3.42(s,1H),2.40(s,3H),1.20(d,J＝6.8Hz,6H)。 1 H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 8.41 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.0 Hz 1H), 7.92 (d, J = 7.8 Hz 1H), 7.63 (d, J = 8.0 Hz, 2H), 4.36 (s, 1H), 3.93 (s, 2H), 3.53-3.45 (m, 1H), 3.42 (s, 1H), 2.40 (s, 3H), 1.20 (d, J = 6.8 Hz, 6H).

实施例6：3-氨基-N-(5-氟-4-(4-(氧杂环丁基-3-基)哌嗪-1-基)吡啶-3-基)-6-(4-(异丙基磺酰基)苯基)吡唑-2-甲酰胺(6)的制备
Example 6: Preparation of 3-amino-N-(5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (6)

步骤1：1-(3-氟-5-硝基吡啶-4-基)-4-(氧杂环丁烷-3-基)哌嗪(6-2)的制备Step 1: Preparation of 1-(3-fluoro-5-nitropyridin-4-yl)-4-(oxetane-3-yl)piperazine (6-2)

将化合物A1(200mg,0.91mmol,1.0eq.)、1-(氧杂环丁烷-3-基)哌嗪(6-1)(129mg,0.91mmol,1.0eq.)、TEA(235mg,1.82mmol,2.0eq.)溶解在DMF(5mL)中，25℃搅拌4小时。反应混合物加水20mL搅拌10分钟，再加入20mL乙酸乙酯继续搅拌5分钟，乙酸乙酯萃取三次，合并有机相，并用饱和食盐水30mL洗涤有机相，无水硫酸钠干燥，过滤，减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：MeOH/DCM＝0％～5％)纯化，得到黄色粉末状化合物6-2，220mg(收率：89.5％)。 Compound A1 (200 mg, 0.91 mmol, 1.0 eq.), 1-(oxetane-3-yl)piperazine (6-1) (129 mg, 0.91 mmol, 1.0 eq.), and TEA (235 mg, 1.82 mmol, 2.0 eq.) were dissolved in DMF (5 mL) and stirred at 25°C for 4 hours. 20 mL of water was added to the reaction mixture and stirred for 10 minutes, and then 20 mL of ethyl acetate was added and stirred for 5 minutes. The mixture was extracted with ethyl acetate three times, the organic phases were combined, and the organic phases were washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: MeOH/DCM = 0% to 5%) to obtain yellow powder compound 6-2, 220 mg (yield: 89.5%).

步骤2：5-氟-4-(4-(氧杂环丁烷-3-基)哌嗪-1-基)吡啶-3-胺(6-3)的制备Step 2: Preparation of 5-fluoro-4-(4-(oxetane-3-yl)piperazin-1-yl)pyridin-3-amine (6-3)

在50mL的单口瓶中加入化合物6-2(220mg,0.79mmol,1.0eq.)，再加入Pd/C 44mg(20％)，加入35mL甲醇，氢气氛下，室温搅拌10小时。反应液经硅藻土过滤，并用4mL甲醇洗涤滤饼，滤液减压浓缩，得到化合物6-3(170mg，收率：86.7％)。Add compound 6-2 (220 mg, 0.79 mmol, 1.0 eq.) to a 50 mL single-mouth bottle, then add Pd/C 44 mg (20%), add 35 mL methanol, and stir at room temperature for 10 hours under hydrogen atmosphere. The reaction solution is filtered through diatomaceous earth, and the filter cake is washed with 4 mL methanol. The filtrate is concentrated under reduced pressure to obtain compound 6-3 (170 mg, yield: 86.7%).

步骤3：3-氨基-N-(5-氟-4-(4-(氧杂环丁基-3-基)哌嗪-1-基)吡啶-3-基)-6-(4-(异丙基磺酰基)苯基)吡唑-2-甲酰胺(6)的制备Step 3: Preparation of 3-amino-N-(5-fluoro-4-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (6)

将化合物A2(50mg,0.16mmol,1.0eq.)、化合物6-3(53mg,0.21mmol,1.3eq.)、HATU(80mg,0.21mmol,1.3eq.)、DIPEA(42mg,0.32mmol,2.0eq.)溶解在DMF(2.5mL)中，25℃搅拌14小时。反应混合物加水2mL搅拌10分钟，再加入6mL水继续搅拌10分钟，混合物过滤，滤饼用2mL甲醇淋洗，再用2mL乙酸乙酯淋洗，收集滤饼，并干燥，得到黄色固体状化合物6，37mg(收率43％，纯度96％)。Compound A2 (50 mg, 0.16 mmol, 1.0 eq.), compound 6-3 (53 mg, 0.21 mmol, 1.3 eq.), HATU (80 mg, 0.21 mmol, 1.3 eq.), and DIPEA (42 mg, 0.32 mmol, 2.0 eq.) were dissolved in DMF (2.5 mL) and stirred at 25°C for 14 hours. 2 mL of water was added to the reaction mixture and stirred for 10 minutes, and then 6 mL of water was added and stirred for 10 minutes. The mixture was filtered, and the filter cake was rinsed with 2 mL of methanol and then with 2 mL of ethyl acetate. The filter cake was collected and dried to obtain 37 mg of compound 6 as a yellow solid (yield 43%, purity 96%).

LCMS(ESI)m/z 556,(M+H)+。LCMS (ESI) m/z 556, (M+H) + .

1H NMR(400MHz,DMSO)δ10.56(s,1H),9.24(s,1H),9.14(s,1H),8.72(s,1H),8.47(d,4H),8.14–7.82(m,5H),7.83(d,2H),4.40(m,1H),4.11(m,1H),3.66(m,5H),3.47(m,2H),3.27(m,3H),3.14(m,3H),2.65(m,5H),2.40(m,5H),2.05(s,1H),1.93(s,6H),1.61(d,2H),1.22(s,6H)。 1 H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.24 (s, 1H), 9.14 (s, 1H), 8.72 (s, 1H), 8.47 (d, 4H), 8.14–7.82 (m, 5H), 7.83 (d, 2H), 4.40 (m, 1H), 4.11 (m, 1H), 3.66 (m, 5H), 3.47 (m, 2H), 3.27 (m, 3H), 3.14 (m, 3H), 2.65 (m, 5H), 2.40 (m, 5H), 2.05 (s, 1H), 1.93 (s, 6H), 1.61 (d, 2H), 1.22 (s, 6H).

参照实施例6的合成方法制备以下化合物：











The following compounds were prepared by the synthetic method of Example 6:











实施例8：3-氨基-N-(4-(4-(乙基氨基甲酰基)哌啶-1-基)-5-氟吡啶-3-基)-6-(4-(异丙基磺酰基)苯基)吡唑-2-甲酰胺(8)的制备

Example 8: Preparation of 3-amino-N-(4-(4-(ethylcarbamoyl)piperidin-1-yl)-5-fluoropyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (8)

将化合物A3(100mg,0.18mmol)、乙胺盐酸盐(18mg，0.22mmol)溶解在DMF(2ml)中，加入HATU(84mg，0.22mmol)、DIPEA(46mg，0.36mmol)，氮气氛下，室温反应3小时。向反应液中滴加水(6ml)，有固体析出，过滤，滤饼用少量水淋洗，烘干得到化合物8(68mg，黄色固体，收率65％)。Compound A3 (100 mg, 0.18 mmol) and ethylamine hydrochloride (18 mg, 0.22 mmol) were dissolved in DMF (2 ml), and HATU (84 mg, 0.22 mmol) and DIPEA (46 mg, 0.36 mmol) were added. The mixture was reacted at room temperature for 3 hours under a nitrogen atmosphere. Water (6 ml) was added dropwise to the reaction solution, and solids were precipitated. The solids were filtered, and the filter cake was rinsed with a small amount of water and dried to obtain compound 8 (68 mg, yellow solid, yield 65%).

LCMS(ESI)m/z 570.3,(M+H)+。LCMS (ESI) m/z 570.3, (M+H) + .

1H NMR(400MHz,DMSO)δ10.51(s,1H),9.28(s,1H),9.10(s,1H),8.37(dd,J＝18.7,5.8Hz,3H),8.09–7.88(m,4H),7.78(t,J＝5.4Hz,1H),3.59(dt,J＝13.5,6.7Hz,1H),3.26–3.18(m,2H),3.05(dd,J＝7.1,5.6Hz,4H),2.31–2.22(m,1H),1.87–1.77(m,4H),1.20(d,J＝6.8Hz,6H),0.99(t,J＝7.2Hz,3H)。 1 H NMR (400 MHz, DMSO) δ 10.51 (s, 1H), 9.28 (s, 1H), 9.10 (s, 1H), 8.37 (dd, J = 18.7, 5.8 Hz, 3H), 8.09–7.88 (m, 4H), 7.78 (t, J = 5.4 Hz, 1H), 3.59 (dt, J = 13.5, 6.7 Hz, 1H), 3.26–3.18 (m, 2H), 3.05 (dd, J = 7.1, 5.6 Hz, 4H), 2.31–2.22 (m, 1H), 1.87–1.77 (m, 4H), 1.20 (d, J = 6.8 Hz, 6H), 0.99 (t, J = 7.2 Hz, 3H).

参照实施例8的合成方法制备以下如下化合物












The following compounds were prepared according to the synthesis method of Example 8:












实施例54：3-氨基-6-(4-(异丙基磺酰基)苯基)-N-(4-(4-(甲基氨基甲酰基)哌啶-1-基)-6-氧代-1,6-二氢吡啶-3-基)吡唑-2-甲酰胺(54)的制备
Example 54: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-(4-(4-(methylcarbamoyl)piperidin-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)pyrazole-2-carboxamide (54)

步骤1：1-(2-羟基-5-硝基吡啶-4-基)-N-甲基哌啶-4-甲酰胺(54-3)的制备Step 1: Preparation of 1-(2-hydroxy-5-nitropyridin-4-yl)-N-methylpiperidine-4-carboxamide (54-3)

室温，将4-氯-5-硝基吡啶-2-醇(54-1)(200mg,1.15mmol,1.0eq.)、N-甲基哌啶-4-甲酰胺盐酸盐(54-2)(246mg,1.37mmol,1.2eq.)、三乙胺(0.48mL,3.45mmol,3eq.)依次加入到DMF(5mL)中。反应混合物于40℃搅拌16小时。减压浓缩，所得残余物通过硅胶柱层析色谱法(洗脱剂：(二氯甲烷：甲醇＝4：1)/二氯甲烷＝0～29％) 纯化，得到化合物54-3(330mg，产率100％)。At room temperature, 4-chloro-5-nitropyridine-2-ol (54-1) (200 mg, 1.15 mmol, 1.0 eq.), N-methylpiperidine-4-carboxamide hydrochloride (54-2) (246 mg, 1.37 mmol, 1.2 eq.), and triethylamine (0.48 mL, 3.45 mmol, 3 eq.) were added to DMF (5 mL) in sequence. The reaction mixture was stirred at 40°C for 16 hours. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: (dichloromethane: methanol = 4:1)/dichloromethane = 0-29%). Purification gave compound 54-3 (330 mg, yield 100%).

步骤2：1-(5-氨基-2-羟基吡啶-4-基)-N-甲基哌啶-4-甲酰胺(54-4)的制备Step 2: Preparation of 1-(5-amino-2-hydroxypyridin-4-yl)-N-methylpiperidine-4-carboxamide (54-4)

室温，将化合物54-3(330mg,1.2mmol,1.0eq.)、钯/碳(10wt.％，钯负载量)(100mg)依次加入到THF/DMF/H2O(10mL/5mL/1mL)中。反应混合物于氢气氛下20℃搅拌16小时。减压浓缩，所得残余物通过硅胶柱层析色谱法(洗脱剂：(二氯甲烷:甲醇＝4:1)/二氯甲烷＝0～78％)纯化，得到化合物54-4(130mg,产率43.8％)。Compound 54-3 (330 mg, 1.2 mmol, 1.0 eq.) and palladium/carbon (10 wt.%, palladium loading) (100 mg) were added to THF/DMF/H 2 O (10 mL/5 mL/1 mL) in sequence at room temperature. The reaction mixture was stirred at 20° C. for 16 hours under a hydrogen atmosphere. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: (dichloromethane: methanol = 4:1)/dichloromethane = 0-78%) to obtain compound 54-4 (130 mg, yield 43.8%).

步骤3：3-氨基-6-(4-(异丙基磺酰基)苯基)-N-(4-(4-(甲基氨基甲酰基)哌啶-1-基)-6-氧代-1,6-二氢吡啶-3-基)吡唑-2-甲酰胺(54)的制备Step 3: Preparation of 3-amino-6-(4-(isopropylsulfonyl)phenyl)-N-(4-(4-(methylcarbamoyl)piperidin-1-yl)-6-oxo-1,6-dihydropyridin-3-yl)pyrazole-2-carboxamide (54)

室温，将HATU(100mg,0.26mmol,1.2eq.)慢慢加入到化合物54-4(66mg,0.26mmol,1.2eq.)、化合物A2(73mg,0.22mmol,1.0eq.)和DIPEA(0.12mL,0.66mmol,3.0eq.)的DMF(2.0mL)溶液中，反应液于30℃搅拌6小时。反应液冷却至室温，加水(2mL)搅拌10分钟，过滤，滤饼用甲醇(2mL)淋洗，再用EA(2mL)淋洗，收集滤饼，减压干燥，得到化合物54(45mg，产率36％，纯度96.7％)。At room temperature, HATU (100 mg, 0.26 mmol, 1.2 eq.) was slowly added to a DMF (2.0 mL) solution of compound 54-4 (66 mg, 0.26 mmol, 1.2 eq.), compound A2 (73 mg, 0.22 mmol, 1.0 eq.) and DIPEA (0.12 mL, 0.66 mmol, 3.0 eq.), and the reaction solution was stirred at 30°C for 6 hours. The reaction solution was cooled to room temperature, water (2 mL) was added and stirred for 10 minutes, filtered, the filter cake was rinsed with methanol (2 mL), and then with EA (2 mL), the filter cake was collected, and dried under reduced pressure to obtain compound 54 (45 mg, yield 36%, purity 96.7%).

LCMS(ESI)m/z 554.2,(M+H)+。LCMS (ESI) m/z 554.2, (M+H) + .

1H NMR(400MHz,DMSO)δ11.20(s,1H),9.88(s,1H),9.08(s,1H),8.41(d,J＝8.3Hz,2H),8.03-7.84(m,4H),7.72(d,J＝4.6Hz,1H),5.94(s,1H),3.59(dt,J＝13.9,7.0Hz,1H),3.31-3.28(m,4H),2.62(dd,J＝25.1,16.6Hz,3H),2.20(d,J＝26.6Hz,1H),1.77(s,4H),1.23(d,J＝6.8Hz,6H)。 1 H NMR (400 MHz, DMSO) δ 11.20 (s, 1H), 9.88 (s, 1H), 9.08 (s, 1H), 8.41 (d, J = 8.3 Hz, 2H), 8.03-7.84 (m, 4H), 7.72 (d, J = 4.6 Hz, 1H), 5.94 (s, 1H), 3.59 (dt, J = 13.9, 7.0 Hz, 1H), 3.31-3.28 (m, 4H), 2.62 (dd, J = 25.1, 16.6 Hz, 3H), 2.20 (d, J = 26.6 Hz, 1H), 1.77 (s, 4H), 1.23 (d, J = 6.8 Hz, 6H).

实施例85：3-氨基-N-(5-氨基甲酰基-4-(4-(甲氨基甲酰基)哌啶-1-基)吡啶-3-基)-6-(4-(异丙基磺酰基)苯基)吡唑-2-甲酰胺(85)的制备
Example 85: Preparation of 3-amino-N-(5-carbamoyl-4-(4-(methylcarbamoyl)piperidin-1-yl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (85)

化合物56(60mg，0.1mmol，1.0eq)加入到1ml浓硫酸中，常温搅拌12h。将反应液滴入冰水里，加入碳酸钠将溶液调成碱性，加入DCM和水萃取后纯化，得 到化合物85(18.7mg，纯度100％)。Compound 56 (60 mg, 0.1 mmol, 1.0 eq) was added to 1 ml of concentrated sulfuric acid and stirred at room temperature for 12 h. The reaction solution was dropped into ice water, sodium carbonate was added to make the solution alkaline, and DCM and water were added for extraction and purification to obtain To obtain compound 85 (18.7 mg, purity 100%).

LCMS(ESI)m/z 582.2,(M+H)+。LCMS (ESI) m/z 582.2, (M+H) + .

1H NMR(400MHz,DMSO)δ10.30(s,1H),9.21(s,1H),9.13(s,1H),8.44(d,J＝8.4Hz,2H),8.28(s,1H),8.17(s,1H),8.02(d,J＝8.5Hz,3H),7.74(s,1H),7.67(d,J＝4.6Hz,1H),3.56(dt,J＝13.7,6.8Hz,1H),3.16(d,J＝13.0Hz,5H),2.26–2.13(m,1H),1.81(d,J＝3.8Hz,4H),1.26(d,J＝6.8Hz,7H)。 1 H NMR (400 MHz, DMSO) δ 10.30 (s, 1H), 9.21 (s, 1H), 9.13 (s, 1H), 8.44 (d, J = 8.4 Hz, 2H), 8.28 (s, 1H), 8.17 (s, 1H), 8.02 (d, J = 8.5 Hz, 3H), 7.74 (s, 1H), 7.67 (d, J = 4.6 Hz, 1H), 3.56 (dt, J = 13.7, 6.8 Hz, 1H), 3.16 (d, J = 13.0 Hz, 5H), 2.26–2.13 (m, 1H), 1.81 (d, J = 3.8 Hz, 4H), 1.26 (d, J = 6.8 Hz, 7H).

实施例100：3-氨基-N-(5-氟-4-(4-(3-(哌啶-1-基)氮杂环丁烷-1-羰基)苯基)吡啶-3-基)-6-(4-(异丙基磺酰基)苯基)吡唑-2-甲酰胺(100)的制备
Example 100: Preparation of 3-amino-N-(5-fluoro-4-(4-(3-(piperidin-1-yl)azetidine-1-carbonyl)phenyl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (100)

步骤1：(3-(哌啶-1-基)氮杂环丁烷-1-基)(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)甲酮(100-3)的制备Step 1: Preparation of (3-(piperidin-1-yl)azetidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (100-3)

室温，将HATU(551mg,1.45mmol,1.2eq.)慢慢加入到4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯甲酸(100-1)(300mg,1.21mmol,1.0eq.)、1-(氮杂环丁烷-3-基)哌啶(100-2)(309mg,1.45mmol,1.2eq.)和DIPEA(0.9mL,4.84mmol,4.0eq.)的DMF(6.0mL)溶液中。反应液于30℃搅拌3小时。加入饱和碳酸氢钠水溶液(20.0mL)，用乙酸乙酯(10.0mL x 2)萃取，合并有机相，经饱和食盐水(10.0mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。所得残余物通过硅胶柱层析色谱法(洗脱剂：(二氯甲烷:甲醇＝4:1)/二氯甲烷＝0-16％)纯化，得到化合物100-3(482mg,产率100％)。At room temperature, HATU (551 mg, 1.45 mmol, 1.2 eq.) was slowly added to a DMF (6.0 mL) solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (100-1) (300 mg, 1.21 mmol, 1.0 eq.), 1-(azetidin-3-yl)piperidine (100-2) (309 mg, 1.45 mmol, 1.2 eq.) and DIPEA (0.9 mL, 4.84 mmol, 4.0 eq.). The reaction mixture was stirred at 30°C for 3 hours. Saturated aqueous sodium bicarbonate solution (20.0 mL) was added, and the mixture was extracted with ethyl acetate (10.0 mL x 2). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1)/dichloromethane=0-16%) to obtain compound 100-3 (482 mg, yield 100%).

步骤2：(4-(3-氨基-5-氟吡啶-4-基)苯基)(3-(哌啶-1-基)氮杂环丁烷-1-基)甲酮(100-4)的制备Step 2: Preparation of (4-(3-amino-5-fluoropyridin-4-yl)phenyl)(3-(piperidin-1-yl)azetidin-1-yl)methanone (100-4)

室温，将化合物100-3(30mg,0.158mmol,1.0eq.)、化合物A1(59mg,0.158mmol,1.0eq.)、Pd(dppf)Cl2(13mg,0.016mmol,0.1eq.)和醋酸钾(46.5mg,0.474mmol,3eq.)依次加入到二氧六环/H2O(1.2mL/0.3mL)中。反应混合物于80℃搅拌 16小时。减压浓缩，所得残余物通过硅胶柱层析色谱法(洗脱剂：(二氯甲烷:甲醇＝4:1)/二氯甲烷＝0～32％)纯化，得到化合物100-4(63mg，产率100％)。At room temperature, compound 100-3 (30 mg, 0.158 mmol, 1.0 eq.), compound A1 (59 mg, 0.158 mmol, 1.0 eq.), Pd(dppf)Cl2 (13 mg, 0.016 mmol, 0.1 eq.) and potassium acetate (46.5 mg, 0.474 mmol, 3 eq.) were added to dioxane/H 2 O (1.2 mL/0.3 mL) in sequence. The reaction mixture was stirred at 80°C. 16 hours. Concentrate under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1)/dichloromethane=0-32%) to obtain compound 100-4 (63 mg, yield 100%).

步骤3：3-氨基-N-(5-氟-4-(4-(3-(哌啶-1-基)氮杂环丁烷-1-羰基)苯基)吡啶-3-基)-6-(4-(异丙基磺酰基)苯基)吡唑-2-甲酰胺(100)的制备Step 3: Preparation of 3-amino-N-(5-fluoro-4-(4-(3-(piperidin-1-yl)azetidine-1-carbonyl)phenyl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (100)

室温，将HATU(81mg,0.213mmol,1.2eq.)慢慢加入到化合物100-4(63mg,0.178mmol,1.0eq.)、化合物A2(68.5mg,0.213mmol,1.2eq.)和DIPEA(0.1mL,0.534mmol,3.0eq.)的DMF(2mL)溶液中，反应液于25℃搅拌16小时。反应液中加入饱和碳酸氢钠水溶液(10.0mL)，用乙酸乙酯(10.0mL x 2)萃取，合并有机相，经饱和食盐水(10.0mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。所得残余物通过硅胶柱层析色谱法(洗脱剂：(二氯甲烷:甲醇＝4:1)/二氯甲烷＝0-32％)纯化，得到化合物100(35mg，产率29.9％，纯度98.2％)。At room temperature, HATU (81 mg, 0.213 mmol, 1.2 eq.) was slowly added to a DMF (2 mL) solution of compound 100-4 (63 mg, 0.178 mmol, 1.0 eq.), compound A2 (68.5 mg, 0.213 mmol, 1.2 eq.) and DIPEA (0.1 mL, 0.534 mmol, 3.0 eq.), and the reaction solution was stirred at 25°C for 16 hours. Saturated sodium bicarbonate aqueous solution (10.0 mL) was added to the reaction solution, and extracted with ethyl acetate (10.0 mL x 2). The organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1)/dichloromethane=0-32%) to give Compound 100 (35 mg, yield 29.9%, purity 98.2%).

LCMS(ESI)m/z 658.2(M+H)+。LCMS (ESI) m/z 658.2 (M+H) + .

1H NMR(400MHz,DMSO)δ10.05(s,1H),9.39(s,1H),9.02(s,1H),8.61(s,1H),7.94–7.85(m,8H),7.71(d,J＝7.9Hz,2H),4.31-4.05(m,2H),3.58–3.49(m,1H),3.28-2.99(m,3H),2.52–1.95(m,4H),1.61-1.37(m,6H),1.23(d,J＝6.8Hz,6H)。 1 H NMR (400 MHz, DMSO) δ 10.05 (s, 1H), 9.39 (s, 1H), 9.02 (s, 1H), 8.61 (s, 1H), 7.94–7.85 (m, 8H), 7.71 (d, J=7.9 Hz, 2H), 4.31-4.05 (m, 2H), 3.58–3.49 (m, 1H), 3.28-2.99 (m, 3H), 2.52–1.95 (m, 4H), 1.61-1.37 (m, 6H), 1.23 (d, J=6.8 Hz, 6H).

参照实施例100的合成方法制备以下化合物：

The following compounds were prepared by referring to the synthesis method of Example 100:

实施例101：3-氨基-N-(3,5-二氟-2-(4-(甲基氨基甲酰基)哌啶-1-基)苯基)-6-(4-(异丙基磺酰基)苯基)吡唑-2-甲酰胺(101)的制备
Example 101: Preparation of 3-amino-N-(3,5-difluoro-2-(4-(methylcarbamoyl)piperidin-1-yl)phenyl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (101)

步骤1：1-(2,4-二氟-6-硝基苯基)-N-甲基哌啶-4-甲酰胺(101-3)的制备Step 1: Preparation of 1-(2,4-difluoro-6-nitrophenyl)-N-methylpiperidine-4-carboxamide (101-3)

室温，将2-溴-1,5-二氟-3-硝基苯(101-1)(160mg,0.67mmol,1.2eq.)、化合物54-2(100mg,0.56mmol,1.0eq.)、Pd2(dba)3(77mg,0.08mmol,0.15eq.)、xantphos(65mg,0.112mmol,0.2eq.)和碳酸铯(547mg,1.68mmol,3eq.)依次加入到二氧六环(6mL)中。反应混合物于100℃搅拌16小时。反应液冷却至室温，减压浓缩，所得残余物通过硅胶柱层析色谱法(洗脱剂：(二氯甲烷:甲醇＝4:1)/二氯甲烷＝0～11％)纯化，得到化合物101-3(99mg，产率28.5％，纯度48.3％)。At room temperature, 2-bromo-1,5-difluoro-3-nitrobenzene (101-1) (160 mg, 0.67 mmol, 1.2 eq.), compound 54-2 (100 mg, 0.56 mmol, 1.0 eq.), Pd2(dba)3 (77 mg, 0.08 mmol, 0.15 eq.), xantphos (65 mg, 0.112 mmol, 0.2 eq.) and cesium carbonate (547 mg, 1.68 mmol, 3 eq.) were added to dioxane (6 mL) in sequence. The reaction mixture was stirred at 100 ° C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: (dichloromethane: methanol = 4:1)/dichloromethane = 0-11%) to obtain compound 101-3 (99 mg, yield 28.5%, purity 48.3%).

步骤2：1-(2-氨基-4,6-二氟苯基)-N-甲基哌啶-4-甲酰胺(101-4)的制备Step 2: Preparation of 1-(2-amino-4,6-difluorophenyl)-N-methylpiperidine-4-carboxamide (101-4)

室温，将化合物101-3(99mg,0.33mmol,1.0eq.)、铁粉(93mg,1.65mmol,5eq.)、氯化铵(176mg,3.3mmol,10eq.)依次加入到甲醇/水(6mL/1.5mL)中。反应混合物于65℃搅拌9小时。减压浓缩，所得残余物通过硅胶柱层析色谱法(洗脱剂：(二氯甲烷:甲醇＝4:1)/二氯甲烷＝0～12％)纯化，得到化合物101-4(20mg,产率46.5％)。At room temperature, compound 101-3 (99 mg, 0.33 mmol, 1.0 eq.), iron powder (93 mg, 1.65 mmol, 5 eq.), and ammonium chloride (176 mg, 3.3 mmol, 10 eq.) were added to methanol/water (6 mL/1.5 mL) in sequence. The reaction mixture was stirred at 65 ° C for 9 hours. The residue was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: (dichloromethane: methanol = 4:1)/dichloromethane = 0-12%) to obtain compound 101-4 (20 mg, yield 46.5%).

步骤3：3-氨基-N-(3,5-二氟-2-(4-(甲基氨基甲酰基)哌啶-1-基)苯基)-6-(4-(异丙基磺酰基)苯基)吡唑-2-甲酰胺(101)的制备Step 3: Preparation of 3-amino-N-(3,5-difluoro-2-(4-(methylcarbamoyl)piperidin-1-yl)phenyl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (101)

室温，将HATU(34mg,0.089mmol,1.2eq.)慢慢加入到化合物101-4(20mg,0.074mmol,1.0eq.)、化合物A2(28.6mg,0.089mmol,1.2eq.)和DIPEA(28mg,0.22mmol,3.0eq.)的DMF(1mL)溶液中，反应液于25℃搅拌7小时。反应液冷却至室温，加入饱和碳酸氢钠水溶液(5.0mL)，用乙酸乙酯(10.0mL x 2)萃取，合并有机相，经饱和食盐水(10.0mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。所得残余物通过硅胶柱层析色谱法(洗脱剂：(二氯甲烷:甲醇＝4:1)/二氯甲烷＝0-5.5％)纯化，得到化合物101(12mg，产率28.2％，纯度98.98％)。At room temperature, HATU (34 mg, 0.089 mmol, 1.2 eq.) was slowly added to a DMF (1 mL) solution of compound 101-4 (20 mg, 0.074 mmol, 1.0 eq.), compound A2 (28.6 mg, 0.089 mmol, 1.2 eq.) and DIPEA (28 mg, 0.22 mmol, 3.0 eq.), and the reaction solution was stirred at 25°C for 7 hours. The reaction solution was cooled to room temperature, saturated sodium bicarbonate aqueous solution (5.0 mL) was added, and extracted with ethyl acetate (10.0 mL x 2), and the organic phases were combined, washed with saturated brine (10.0 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: (dichloromethane:methanol=4:1)/dichloromethane=0-5.5%) to give Compound 101 (12 mg, yield 28.2%, purity 98.98%).

LCMS(ESI)m/z 573.2,(M+H)+。LCMS (ESI) m/z 573.2, (M+H) + .

1H NMR(400MHz,DMSO)δ10.92(s,1H),9.09(s,1H),8.36(d,J＝8.4Hz,2H), 8.27(d,J＝11.0Hz,1H),8.07(d,J＝8.2Hz,3H),7.79(t,J＝9.0Hz,1H),7.13–6.97(m,1H),3.56–3.37(m,1H),3.19-2.99(m,4H),2.65(d,J＝4.5Hz,3H),2.35-2.24(m,1H),1.93-1.78(m,4H),1.23(d,J＝6.8Hz,6H)。 1 H NMR (400 MHz, DMSO) δ 10.92 (s, 1H), 9.09 (s, 1H), 8.36 (d, J = 8.4 Hz, 2H), 8.27 (d, J = 11.0 Hz, 1H), 8.07 (d, J = 8.2 Hz, 3H), 7.79 (t, J = 9.0 Hz, 1H), 7.13–6.97 (m, 1H), 3.56–3.37 (m, 1H), 3.19-2.99 (m, 4H), 2.65 (d, J = 4.5 Hz, 3H), 2.35-2.24 (m, 1H), 1.93-1.78 (m, 4H), 1.23 (d, J = 6.8 Hz, 6H).

实施例111：3-氨基-N-(5-(氨基甲基)-4-(4-(甲基氨基甲酰基)哌啶-1-基)吡啶-3-基)-6-(4-(异丙基磺酰基)苯基)吡唑-2-甲酰胺(111)的制备
Example 111: Preparation of 3-amino-N-(5-(aminomethyl)-4-(4-(methylcarbamoyl)piperidin-1-yl)pyridin-3-yl)-6-(4-(isopropylsulfonyl)phenyl)pyrazole-2-carboxamide (111)

化合物56(90mg，0.16mmol，1.0eq)的氨水-甲醇(6ml)溶液中加入雷尼镍(188mg，1.89mmol，20.0eq)，常温反应48h。将反应液通过制备高效液相色谱法纯化(流动相为水/乙腈＝100％-70％/30％，梯度淋洗，流动相中按体积百分比添加0.1％甲酸，流速为20.0mL/min)，得到化合物111(19.2mg，产率22％)。Raney nickel (188 mg, 1.89 mmol, 20.0 eq) was added to a solution of compound 56 (90 mg, 0.16 mmol, 1.0 eq) in aqueous ammonia-methanol (6 ml), and the mixture was reacted at room temperature for 48 h. The reaction solution was purified by preparative high performance liquid chromatography (mobile phase: water/acetonitrile = 100%-70%/30%, gradient elution, 0.1% formic acid was added to the mobile phase by volume, flow rate: 20.0 mL/min), to obtain compound 111 (19.2 mg, yield 22%).

LCMS(ESI)m/z 567,(M+H)+。LCMS (ESI) m/z 567, (M+H) + .

1H NMR(400MHz,DMSO)δ10.39(s,1H),9.08(d,J＝5.1Hz,1H),8.87(s,1H),8.49–8.38(m,3H),8.34(s,1H),7.96(d,J＝8.5Hz,4H),7.71–7.59(m,1H),4.29(d,J＝5.5Hz,1H),3.87(s,2H),3.60–3.45(m,2H),3.17(s,5H),2.19(s,2H),1.76(s,5H),1.22(d,J＝6.8Hz,6H)。 1 H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 9.08 (d, J = 5.1 Hz, 1H), 8.87 (s, 1H), 8.49–8.38 (m, 3H), 8.34 (s, 1H), 7.96 (d, J = 8.5 Hz, 4H), 7.71–7.59 (m, 1H), 4.29 (d, J = 5.5 Hz, 1H), 3.87 (s, 2H), 3.60–3.45 (m, 2H), 3.17 (s, 5H), 2.19 (s, 2H), 1.76 (s, 5H), 1.22 (d, J = 6.8 Hz, 6H).

生物学测试Biological tests

试验例1：ATR体外酶学活性抑制实验Test Example 1: ATR in vitro enzyme activity inhibition experiment

使用HTRF检测技术评估化合物对ATR激酶(Eurofins-14-953M)的抑制作用，带有GST标签的P53蛋白(Eurofins-14-952M)用作底物。使用含1.25mM MnCl2、50nM SEB和1mM DTT的1x激酶试验缓冲液(cisbio)稀释化合物(0-10000nM)和ATR激酶。室温下将化合物和每孔30ng的ATR激酶混合孵育15分钟。通过加入500nM的P53和3.91uM的ATP来启动反应，总反应体系为10uL。在室温持续反应90 分钟，然后加入10uL含Mab Anti-phospho P53-Eu cryptate(cisbio-61P08KAZ)和Mab Anti GST-d2(cisbio-61GSTDLB)的检测溶液，室温下反应1小时。HTRF信号使用Tecan spark多功能酶标仪收集620nm和665nm波长信号值，用于计算化合物对ATR激酶抑制的IC50值。表1报道了每个化合物ATR酶学活性抑制结果。The inhibitory effect of the compounds on ATR kinase (Eurofins-14-953M) was evaluated using HTRF detection technology. GST-tagged P53 protein (Eurofins-14-952M) was used as substrate. Compounds (0-10000nM) and ATR kinase were diluted in 1x kinase assay buffer (cisbio) containing 1.25mM MnCl2 , 50nM SEB and 1mM DTT. Compounds were mixed with 30ng of ATR kinase per well and incubated for 15 minutes at room temperature. The reaction was initiated by adding 500nM P53 and 3.91uM ATP. The total reaction volume was 10uL. The reaction was continued at room temperature for 90 Minutes, then 10uL of detection solution containing Mab Anti-phospho P53-Eu cryptate (cisbio-61P08KAZ) and Mab Anti GST-d2 (cisbio-61GSTDLB) was added and reacted at room temperature for 1 hour. HTRF signals were collected using a Tecan spark multifunctional microplate reader at 620nm and 665nm wavelengths to calculate the IC 50 value of the compound's inhibition of ATR kinase. Table 1 reports the results of each compound's ATR enzymatic activity inhibition.

表1本发明化合物抑制ATR激酶的IC50值
Table 1 IC 50 values of the compounds of the present invention for inhibiting ATR kinase

结论：在ATR酶活抑制实验中，本发明的化合物表现出较强的抑制活性。Conclusion: In the ATR enzyme activity inhibition experiment, the compounds of the present invention showed strong inhibitory activity.

试验例2：本发明化合物对22RV1(人前列腺癌细胞)和MDA-MB-436(乳腺癌细胞)细胞增殖活性抑制实验Test Example 2: Experimental study on the inhibitory activity of the compounds of the present invention on 22RV1 (human prostate cancer cells) and MDA-MB-436 (breast cancer cells) cells proliferation

将22RV1细胞(购于南京科佰生物科技有限公司)和MDA-MB-436细胞(购于南京科佰生物科技有限公司)按照每孔5000的密度接种至96孔板中。第二天将化合物从10000nM起始4倍稀释8个梯度，将化合物加入96孔板对应孔中，置于37℃培养箱培养72h。将细胞板平衡至室温，然后每孔加入50uL的CellTiter-Glo溶液，室温反应10分钟后在biotek H1多功能酶标仪上读取化学发光信号，然后使用xlfit软件对结果进行分析，计算化合物对22RV1和MDA-MB-436细胞活力的抑制效率。表2报道了化合物对22RV1和MDA-MB-436细胞的细胞增殖抑制结果。22RV1 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) and MDA-MB-436 cells (purchased from Nanjing Kebai Biotechnology Co., Ltd.) were seeded into 96-well plates at a density of 5000 per well. The next day, the compound was diluted 4-fold from 10000nM into 8 gradients, and the compound was added to the corresponding wells of the 96-well plate and cultured in a 37°C incubator for 72 hours. The cell plate was equilibrated to room temperature, and then 50uL of CellTiter-Glo solution was added to each well. After reacting at room temperature for 10 minutes, the chemiluminescent signal was read on the biotek H1 multifunctional microplate reader, and then the results were analyzed using xlfit software to calculate the inhibitory efficiency of the compound on the viability of 22RV1 and MDA-MB-436 cells. Table 2 reports the results of the compound's inhibition of cell proliferation of 22RV1 and MDA-MB-436 cells.

表2本发明化合物对22RV1和MDA-MB-436细胞的细胞增殖抑制IC50值
Table 2 IC 50 values of the compounds of the present invention for inhibiting cell proliferation of 22RV1 and MDA-MB-436 cells

结论：本发明化合物对22RV1(人前列腺癌细胞)和MDA-MB-436(乳腺癌细胞)具有较好的细胞增殖抑制活性。 Conclusion: The compounds of the present invention have good cell proliferation inhibitory activity against 22RV1 (human prostate cancer cells) and MDA-MB-436 (breast cancer cells).

Claims (22)

一种通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
A compound represented by general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in: R1选自氢、烷基、烯基、炔基，所述烷基、烯基、炔基任选被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷氧基、卤羟烷基、烯基、炔基的一个或多个取代基所取代；R 1 is selected from hydrogen, alkyl, alkenyl, alkynyl, and the alkyl, alkenyl, alkynyl is optionally substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkoxy, halohydroxyalkyl, alkenyl, alkynyl; 或者，R1为 Alternatively, R1 is 其中：in: L选自键、亚烷基、亚烯基、亚炔基、-C(O)-、-S(O)-、-S(O)2-、-C(O)NH-、-S(O)NH-、-S(O)2NH-、-C(O)O-；L is selected from a bond, alkylene, alkenylene, alkynylene, -C(O)-, -S(O)-, -S(O) 2- , -C (O)NH-, -S(O)NH-, -S(O)2NH-, -C(O)O-; 环A选自芳基、杂芳基、环烷基或杂环基，所述芳基、杂芳基、环烷基或杂环基任选被一个或多个Q基团取代；Ring A is selected from aryl, heteroaryl, cycloalkyl or heterocyclyl, and the aryl, heteroaryl, cycloalkyl or heterocyclyl is optionally substituted with one or more Q groups; Q选自氢、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRc(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRc(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc的一个或多个取代基所取代；Q is selected from hydrogen, halogen, amino, hydroxyl, thiol, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl, heteroaryl , -( CH2 ) qNRaRb , - ( CH2 )qRc, -( CH2 )qORc , -( CH2 ) qC (O) Rc , -( CH2 ) qC (O) ORc , -( CH2 ) qOC (O) Rc , -( CH2 ) qC ( O )NRaRb, - ( CH2 ) qS ( O ) pRc , -( CH2 ) qS ( O) pNRaRb , -NRc ( O) NRaRb , -( CH2 ) qNRaC (O) Rc , -( CH2 ) qNRa wherein the alkyl , alkoxy , alkenyl, alkynyl, cycloalkyl, heterocyclyl , aryl and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy , haloalkoxy, hydroxyalkyl, alkenyl , alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) qNRaRb , -( CH2 ) qRc , -( CH2 )qORc, -( CH2 ) qC ( O ) Rc , -( CH2 ) qC (O) ORc , - ( CH2 ) qOC (O) Rc , -( CH2 ) qC (O) NRaRb , -C(O) NRc ( CH2 ) q NR a R b , -(CH 2 ) q S(O) p R c , -(CH 2 ) q S(O) p NR a R b , -NR c (O)NR a R b , -(CH 2 ) q NR a C(O)R c , -(CH 2 ) q NR a C(O)OR c or -(CH 2 ) q NR a S(O) p R c ; R2选自氢、卤素、烷基、烯基、炔基，所述烷基、烯基、炔基任选被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧 基、卤代烷氧基、羟烷基、烯基、炔基的一个或多个取代基所取代； R2 is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, wherein the alkyl, alkenyl, alkynyl is optionally selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy substituted by one or more substituents of alkyl, haloalkoxy, hydroxyalkyl, alkenyl, or alkynyl; 或者，R1和R2与其相连的氮原子一起形成杂环基或杂芳基，所述杂环基或杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb的一个或多个取代基所取代；Alternatively, R1 and R2 together with the nitrogen atom to which they are attached form a heterocyclic group or a heteroaryl group, which is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group , aryl, heteroaryl , -( CH2 ) qNRaRb ; R3选自烷基、卤代烷基或环烷基； R3 is selected from alkyl, haloalkyl or cycloalkyl; 每个R4各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤烷氧基、卤羟烷基、烯基、炔基、烷基磺酰基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；each R 4 is independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkoxy, halohydroxyalkyl, alkenyl, alkynyl, alkylsulfonyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Ra和Rb各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；R a and R b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q NR d R e , -(CH 2 ) q R f , -(CH 2 ) q OR f , -(CH 2 ) q C (O)R f , -(CH 2 ) q C(O)OR f , - ( CH 2 ) q OC(O)R f , -(CH 2 ) q -C(O)NR d R e , -C(O)NR f (CH 2 ) q NR d R e , -(CH 2 ) q S(O) p R f , -(CH 2 ) q S(O) p NR d R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O)R f , -(CH 2 ) q NR d C(O)OR f or -(CH 2 ) q NR d S(O) p R f ; 或者，Ra和Rb与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl , mercapto, alkyl , alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl , -( CH2 ) qNRdRe , -( CH2 ) qRf , -( CH2 ) qORf , - ( CH2 ) qC (O) Rf , -(CH2) qC (O) ORf , -( CH2 ) qOC (O) Rf , -(CH2)qC(O)NRdRe, -C(O)NRf(CH2)qNRdRe , - ( CH2 ) qS ( O ) pRf , - ( CH2 ) qS (O) pNRd R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O) R f , -(CH 2 ) q NR d C(O) OR f or -(CH 2 ) q NR d S(O) p R f substituted with one or more substituents; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; Rc选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R c is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Rd和Re各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、氨酰基、烷基氨酰基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R d and Re are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; 或者，Rd和Re与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、二烷基氨基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个取代基所取代，所述环烷基和杂环基任选进一步被选自卤素、烷基、卤代烷基的一个或多个基团所取代；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl; Rf选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; m为0、1、2或3；m is 0, 1, 2 or 3; p为0、1或2；p is 0, 1, or 2; q为0至6的整数。q is an integer from 0 to 6. 根据权利要求1所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，The compound represented by the general formula (I) according to claim 1 or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: R1为 R1 is 其中：in: L选自键、亚烷基、亚烯基、亚炔基、-C(O)-、-S(O)-、-S(O)2-、-C(O)NH-、-S(O)NH-、-S(O)2NH-、-C(O)O-；优选自键、亚烷基、-C(O)-；L is selected from a bond, an alkylene group, an alkenylene group, an alkynylene group, -C(O)-, -S(O)-, -S(O) 2 -, -C(O)NH-, -S(O)NH-, -S(O) 2 NH-, -C(O)O-; preferably selected from a bond, an alkylene group, -C(O)-; 环A选自芳基、杂芳基，优选C6-10芳基或5-10元杂芳基；所述芳基、杂芳基任选被一个或多个Q基团取代；Ring A is selected from aryl, heteroaryl, preferably C 6-10 aryl or 5-10 membered heteroaryl; the aryl, heteroaryl is optionally substituted by one or more Q groups; Q选自氢、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝 基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc的一个或多个取代基所取代；Q is selected from hydrogen, halogen, amino, hydroxyl, thiol, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl , cycloalkyl, heterocyclyl, aryl, heteroaryl , -( CH2 ) qNRaRb , - ( CH2 )qRc, -( CH2 )qORc , -( CH2 ) qC (O) Rc , -( CH2 ) qC (O) ORc , -( CH2 ) qOC (O) Rc , -( CH2 ) qC ( O ) NRaRb , - ( CH2 ) qS ( O ) pRc , -( CH2 ) qS (O ) pNRaRb , -NRcC ( O) NRaRb , - ( CH2 ) qNRaC ( O) Rc , -( CH2 ) qNRa C(O)OR c or -(CH 2 ) q NR a S(O) p R c ; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro R c, -(CH 2 ) q C(O)R c, -(CH 2 ) q C(O)OR c, -(CH 2 ) q OC( O ) R c , -(CH 2 ) q C (O) NR a R b , -C(O) NR c (CH 2 ) q NR a R b , -(CH 2 ) q S (O) p R c, -(CH 2 ) q S(O) p NR a R b , -NR c C ( O ) NR a R b , - ( CH 2 ) q NR aC (O)R c , -(CH 2 ) q NR a C(O)OR c or -(CH 2 ) q NR a S(O) p R c ; Ra和Rb各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；R a and R b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q NR d R e , -(CH 2 ) q R f , -(CH 2 ) q OR f , -(CH 2 ) q C (O)R f , -(CH 2 ) q C(O)OR f , - ( CH 2 ) q OC(O)R f , -(CH 2 ) q -C(O)NR d R e , -C(O)NR f (CH 2 ) q NR d R e , -(CH 2 ) q S(O) p R f , -(CH 2 ) q S(O) p NR d R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O)R f , -(CH 2 ) q NR d C(O)OR f or -(CH 2 ) q NR d S(O) p R f ; 或者，Ra和Rb与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl , mercapto, alkyl , alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl , -( CH2 ) qNRdRe , -( CH2 ) qRf , -( CH2 ) qORf , - ( CH2 ) qC (O) Rf , -(CH2) qC (O) ORf , -( CH2 ) qOC (O) Rf , -(CH2)qC(O)NRdRe, -C(O)NRf(CH2)qNRdRe , - ( CH2 ) qS ( O ) pRf , - ( CH2 ) qS (O) pNRd R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O) R f , -(CH 2 ) q NR d C(O) OR f or -(CH 2 ) q NR d S(O) p R f substituted with one or more substituents; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; Rc选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R c is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Rd和Re各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、氨酰基、烷基氨酰基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R d and Re are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; 或者，Rd和Re与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、二烷基氨基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个取代基所取代，所述环烷基和杂环基任选进一步被选自卤素、烷基、卤代烷基的一个或多个基团所取代；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl; Rf选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; p为0、1或2；p is 0, 1, or 2; q为0至6的整数。q is an integer from 0 to 6. 根据权利要求1或2所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(II)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
The compound represented by the general formula (I) according to claim 1 or 2, or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,
其中：in: L选自键、亚烷基、-C(O)-；优选为键；L is selected from a bond, an alkylene group, -C(O)-; preferably a bond; X1、X2、X3、X4各自独立地选自CH或N；X 1 , X 2 , X 3 , and X 4 are each independently selected from CH or N; Q1选自氢、卤素、氨基、羟基、巯基、硝基、氰基、氧代基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、-(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc；所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRaRb、-(CH2)qRc、-(CH2)qORc、 -(CH2)qC(O)Rc、-(CH2)qC(O)ORc、-(CH2)qOC(O)Rc、-(CH2)qC(O)NRaRb、-C(O)NRc(CH2)qNRaRb、-(CH2)qS(O)pRc、-(CH2)qS(O)pNRaRb、-NRcC(O)NRaRb、-(CH2)qNRaC(O)Rc、-(CH2)qNRaC(O)ORc或-(CH2)qNRaS(O)pRc的一个或多个取代基所取代； Q is selected from hydrogen, halogen, amino, hydroxy, mercapto, nitro, cyano, oxo, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl , heteroaryl , -( CH2 ) qNRaRb , -( CH2 ) qRc , -( CH2 )qORc , -( CH2 ) qC (O) Rc , -( CH2 ) qC (O) ORc , -( CH2 ) qOC (O) Rc , - ( CH2 ) qC ( O ) NRaRb , - ( CH2 ) qS (O) pRc , -( CH2 ) qS ( O)pNRaRb , -NRcC(O)NRaRb, - ( CH2 ) qNRaC ( O) Rc , -( CH2 ) q NR a C(O)OR c or —(CH 2 ) q NR a S(O) p R c ; the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) q NR a R b , —(CH 2 ) q R c , —(CH 2 ) q OR c , -( CH2 ) qC (O) Rc , -( CH2 ) qC (O ) ORc , -( CH2 ) qOC (O) Rc , -( CH2 ) qC (O ) NRaRb , -C (O)NRc ( CH2 )qNRaRb, - ( CH2 ) qS ( O) pRc , -( CH2 ) qS ( O)pNRaRb , -NRcC ( O ) NRaRb , - ( CH2 ) qNRaC(O)Rc, -(CH2)qNRaC ( O ) ORc or - ( CH2 ) qNRaS (O ) pRc ; 每个Q2各自独立地选自氢、卤素、烷基、卤代烷基、-(CH2)qC(O)NRaRb，所述烷基任选进一步被NRaRb取代；Each Q 2 is independently selected from hydrogen, halogen, alkyl, haloalkyl, -(CH 2 ) q C(O)NR a R b , wherein the alkyl is optionally further substituted with NR a R b ; Ra和Rb各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；R a and R b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q NR d R e , -(CH 2 ) q R f , -(CH 2 ) q OR f , -(CH 2 ) q C (O)R f , -(CH 2 ) q C(O)OR f , - ( CH 2 ) q OC(O)R f , -(CH 2 ) q -C(O)NR d R e , -C(O)NR f (CH 2 ) q NR d R e , -(CH 2 ) q S(O) p R f , -(CH 2 ) q S(O) p NR d R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O)R f , -(CH 2 ) q NR d C(O)OR f or -(CH 2 ) q NR d S(O) p R f ; 或者，Ra和Rb与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl , mercapto, alkyl , alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl , -( CH2 ) qNRdRe , -( CH2 ) qRf , -( CH2 ) qORf , - ( CH2 ) qC (O) Rf , -(CH2) qC (O) ORf , -( CH2 ) qOC (O) Rf , -(CH2)qC(O)NRdRe, -C(O)NRf(CH2)qNRdRe , - ( CH2 ) qS ( O ) pRf , - ( CH2 ) qS (O) pNRd R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O) R f , -(CH 2 ) q NR d C(O) OR f or -(CH 2 ) q NR d S(O) p R f substituted with one or more substituents; the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups; Rc选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代；R c is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Rd和Re各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、氨酰基、烷基氨酰基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R d and Re are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; 或者，Rd和Re与其相连的氮原子一起形成杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、二烷基氨基、烯基、炔基、环烷基、杂环基、芳基、杂芳基的一个或多个取代基所取代，所述环烷基和杂环基任选进一步被选自卤素、烷基、卤代烷基的一个或多个基团所取代；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl; Rf选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; n为0、1或2；n is 0, 1 or 2; R2、R3、R4、m、p、q如权利要求1所定义。R 2 , R 3 , R 4 , m, p and q are as defined in claim 1. 根据权利要求3所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，The compound represented by the general formula (I) according to claim 3 or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein: Q1为-NRaRb； Q1 is -NR a R b ; Ra和Rb各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRd(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；R a and R b are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) q NR d R e , -(CH 2 ) q R f , -(CH 2 ) q OR f , -(CH 2 ) q C (O)R f , -(CH 2 ) q C(O)OR f , - ( CH 2 ) q OC(O)R f , -(CH 2 ) q -C(O)NR d R e , -C(O)NR d (CH 2 ) q NR d R e , -(CH 2 ) q S(O) p R f , -(CH 2 ) q S(O) p NR d R e , -NR d C(O)NR d R e , -(CH 2 ) q NR d C(O)R f , -(CH 2 ) q NR d C(O)OR f or -(CH 2 ) q NR d S(O) p R f ; 或者，Ra和Rb与其相连的氮原子一起形成4-10元杂环基，优选4-6元杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、烯基、炔基、C3-6环烷基、3-8元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)qNRdRe、-(CH2)qRf、-(CH2)qORf、-(CH2)qC(O)Rf、-(CH2)qC(O)ORf、-(CH2)qOC(O)Rf、-(CH2)qC(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-(CH2)qS(O)pRf、-(CH2)qS(O)pNRdRe、-NRdC(O)NRdRe、-(CH2)qNRdC(O)Rf、-(CH2)qNRdC(O)ORf或-(CH2)qNRdS(O)pRf中的一个或多个取代基所取代；所述烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Alternatively, Ra and Rb together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclic group, preferably a 4-6 membered heterocyclic group, wherein the heterocyclic group is optionally further selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, alkenyl, alkynyl, C3-6 cycloalkyl, 3-8 membered heterocyclic group, C6-10 aryl, 5-6 membered heteroaryl , -( CH2 ) qNRdRe , -( CH2 ) qRf , -( CH2 ) qORf , -( CH2 ) qC (O) Rf , -( CH2 ) qC (O) ORf , -( CH2 ) qOC (O) Rf , -( CH2 ) qC (O) NRdRe , -C (O) NRf ( CH2 ) qNRdRe , -(CH2) wherein the alkyl , alkenyl , alkynyl , cycloalkyl , heterocyclyl , aryl and heteroaryl groups are optionally substituted by one or more substituents selected from halogen, amino , oxo , thio , nitro , cyano , hydroxyl , thiol, alkyl, haloalkyl , alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups ; Rd和Re各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、氨酰基、烷基氨酰基、烯基、炔基、C3-6环烷基、3至6元杂环基、C6-10芳基和5-6元杂芳基，其中所述烷基、烷氧基、烯基、炔基、C3-6环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、3至6元杂环基、芳基和杂芳基中的一个或多个取代基所取代；R d and Re are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, thiol, alkyl, alkoxy, aminoacyl, alkylaminoacyl, alkenyl, alkynyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl, wherein said alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thioxo, nitro, cyano, hydroxyl, thiol, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3 to 6 membered heterocyclyl, aryl and heteroaryl; 或者，Rd和Re与其相连的氮原子一起形成3-8元杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、二烷基氨基、烯基、炔基、C3-6环烷基、3-8元杂环基、芳基、杂芳基的一个或多个取代基所取代，所述环烷基和杂环基任选进一步被选自卤素、烷基、卤代烷基的一个或多个基团所取代；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more groups selected from halogen, alkyl, haloalkyl; Rf选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; p为1或2；p is 1 or 2; q为0至6的整数，优选1至6的整数，更优选1至4的整数。q is an integer of 0-6, preferably an integer of 1-6, and more preferably an integer of 1-4. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(III)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
A compound represented by the general formula (I) according to any one of claims 1 to 4, or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in: X1、X2、X3、X4各自独立地选自CH或N；优选地，X1为N且X2、X3、X4为CH，或者X2为N且X1、X3、X4为CH，或者X1、X2、X3、X4均为CH； X1 , X2 , X3 , X4 are each independently selected from CH or N; preferably, X1 is N and X2 , X3 , X4 are CH, or X2 is N and X1 , X3 , X4 are CH, or X1 , X2 , X3 , X4 are all CH; Y选自NR5、CR5R6或SO2； Y is selected from NR 5 , CR 5 R 6 or SO 2 ; R5选自氢、卤素、氨基、氧代基、氰基、C1-6烷基、C3-6环烷基、3-8元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)qNRdRe、C(O)Rf、C(O)NRdRe、-C(O)NRf(CH2)qNRdRe、-S(O)pRf、-S(O)pNRdRe、-NRdC(O)Rf；所述C1-6烷基、C3-6环烷基、3-8元杂环基、C6-10芳基和5-6元杂芳基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基中的一个或多个取代基所取代； R5 is selected from hydrogen, halogen, amino, oxo, cyano, C1-6 alkyl, C3-6 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-6 membered heteroaryl, -( CH2 ) qNRdRe , C(O) Rf , C(O) NRdRe , -C(O) NRf ( CH2 ) qNRdRe , -S(O) pRf , -S(O) pNRdRe , -NRdC (O) Rf ; the C1-6 alkyl, C3-6 cycloalkyl , 3-8 membered heterocyclyl, C6-10 aryl and 5-6 membered heteroaryl are optionally further substituted by one or more substituents selected from halogen, C1-6 alkyl and C1-6 haloalkyl; R6选自氢、卤素、氨基和C1-6烷基； R6 is selected from hydrogen, halogen, amino and C1-6 alkyl; 或者，R5和R6与其相连的碳原子一起形成3-12元杂环基，优选3-6元杂环基；所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、烯基、炔基、C3-6环烷基、3-8元杂环基、芳基、杂芳基的一个或多个取代基所取代；Alternatively, R 5 and R 6 together with the carbon atom to which they are attached form a 3-12 membered heterocyclic group, preferably a 3-6 membered heterocyclic group; the heterocyclic group is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl; Rd和Re各自独立地选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、C3-6环烷基、3至6元杂环基、C6-10芳基和5-6元杂芳基，其中所述烷基、烷氧基、烯基、炔基、C3-6环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、3至6元杂环基、芳基和杂芳基中的一个或多个取代基所取代；R d and Re are each independently selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, C 3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, 3 to 6 membered heterocyclyl, aryl and heteroaryl; 或者，Rd和Re与其相连的氮原子一起形成3-8元杂环基，其中所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、二烷基氨基、烯基、炔基、C3-6环烷基、3-8元杂环基、芳基、杂芳基的一个或多个取代基所取代，所述环烷基和杂环基任选进一步被选自卤素、烷基、卤代烷基的一个或多个基团所取代；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, dialkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8 membered heterocyclic group, aryl, heteroaryl, and the cycloalkyl and heterocyclic groups are optionally further substituted with one or more substituents selected from halogen, alkyl, haloalkyl; Rf选自氢、卤素、氨基、硝基、氰基、羟基、巯基、烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； Rf is selected from hydrogen, halogen, amino, nitro, cyano, hydroxyl, mercapto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further substituted with one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; p为1或2；p is 1 or 2; q为1至6的整数，优选1至4的整数，更优选1或2；q is an integer from 1 to 6, preferably an integer from 1 to 4, more preferably 1 or 2; n为0、1或2；n is 0, 1 or 2; s为1或2；优选1；s is 1 or 2; preferably 1; t为1或2；优选1；t is 1 or 2; preferably 1; R2、R3、R4、m如权利要求1所定义；Q2如权利要求3所定义。R 2 , R 3 , R 4 and m are as defined in claim 1 ; Q 2 is as defined in claim 3 . 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IIIA)或(IIIB)所示的化合物或其立体异构 体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
A compound represented by the general formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIA) or (IIIB) or a stereoisomer thereof isomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in: X1、X2各自独立地选自CH或N；X 1 and X 2 are each independently selected from CH or N; Y1选自N或CR6；Y 1 is selected from N or CR 6 ; R6选自氢、卤素、氨基和C1-6烷基； R6 is selected from hydrogen, halogen, amino and C1-6 alkyl; R7选自氢、C1-6烷基、C3-6环烷基、3至6元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)qNRdRe，其中所述C1-6烷基、C3-6环烷基、3至6元杂环基、C6-10芳基、5-6元杂芳基任选进一步被选自卤素、羟基、巯基、C1-6烷基、C1-6卤代烷基、3至6元杂环基的一个或多个取代基所取代；R 7 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, 5 to 6 membered heteroaryl, -(CH 2 ) q NR d R e , wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, C 6-10 aryl, 5 to 6 membered heteroaryl is optionally further substituted with one or more substituents selected from halogen, hydroxyl, mercapto, C 1-6 alkyl, C 1-6 haloalkyl, 3 to 6 membered heterocyclyl; R8选自氢、C1-6烷基、C1-6卤代烷基；R 8 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl; 或者，R7和R8与其相连的氮原子一起形成3-8元杂环基，优选6元杂环基，其中所述杂环基任选进一步被选自卤素、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷基氨基、二C1-6烷基氨基、C3-6环烷基、3-8元杂环基的一个或多个取代基所取代，其中所述C3-6环烷基、3-8元杂环基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基的一个或多个基团所取代；Alternatively, R7 and R8 together with the nitrogen atom to which they are attached form a 3-8 membered heterocyclic group, preferably a 6 membered heterocyclic group, wherein the heterocyclic group is optionally further substituted with one or more substituents selected from halogen, amino, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkylamino, diC1-6 alkylamino, C3-6 cycloalkyl, 3-8 membered heterocyclic group, wherein the C3-6 cycloalkyl, 3-8 membered heterocyclic group is optionally further substituted with one or more substituents selected from halogen, C1-6 alkyl, C1-6 haloalkyl; Rd和Re各自独立地选自氢、C1-6烷基、C3-6环烷基、3至6元杂环基，其中所述C1-6烷基、C3-6环烷基、3至6元杂环基任选进一步被选自卤素的一个或多个取代基所取代；R d and Re are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 3 to 6 membered heterocyclyl is optionally further substituted with one or more substituents selected from halogen; 或者，Rd和Re与其相连的氮原子一起形成3-6元杂环基，其中所述3-6元杂 环基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基的一个或多个取代基所取代；Alternatively, R d and Re together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclic group, wherein the 3-6 membered heterocyclic group The cyclic group is optionally further substituted by one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl; R10选自C1-6烷基、C1-6卤代烷基；R 10 is selected from C 1-6 alkyl, C 1-6 haloalkyl; q为1至4的整数，优选1或2；q is an integer from 1 to 4, preferably 1 or 2; n为0、1或2；n is 0, 1 or 2; R2、R3、R4、m如权利要求1所定义；Q2如权利要求3所定义。R 2 , R 3 , R 4 and m are as defined in claim 1 ; Q 2 is as defined in claim 3 . 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IIIC)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，
A compound represented by the general formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IIIC) or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中：in: X1、X2各自独立地选自CH或N；X 1 and X 2 are each independently selected from CH or N; Y2选自NR11、CR11R12、SO2；Y 2 is selected from NR 11 , CR 11 R 12 , SO 2 ; R12选自氢、卤素、氨基和C1-6烷基；R 12 is selected from hydrogen, halogen, amino and C 1-6 alkyl; R11选自氢、卤素、氧代基、硫代基、氰基、羟基、巯基、C1-6烷基、C3-6环烷基、3-8元杂环基、C6-10芳基、5-6元杂芳基、-(CH2)qNRdRe、-C(O)NRdRe、-S(O)pNRdRe和-NRdC(O)Rf中的一个或多个取代基所取代；所述C1-6烷基、C3-6环烷基、3-8元杂环基、C6-10芳基和5-6元杂芳基任选进一步被选自卤素、C1-6烷基、C1-6卤代烷基中的一个或多个取代基所取代；R 11 is substituted by one or more substituents selected from hydrogen, halogen, oxo, thio, cyano, hydroxyl, mercapto, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, -(CH 2 ) q NR d R e , -C(O)NR d R e , -S(O) p NR d R e and -NR d C(O) R f ; the C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-6 membered heteroaryl are optionally further substituted by one or more substituents selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; 或者，R11和R12与其相连的碳原子一起形成3-12元杂环基，优选3-6元杂环基；所述杂环基任选进一步被选自卤素、氨基、氧代基、硫代基、硝基、氰基、羟基、巯基、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、烷基氨基、烯基、炔基、C3-6环烷基、3-8元杂环基、芳基、杂芳基的一个或多个取代基所取代；Alternatively, R 11 and R 12 together with the carbon atom to which they are attached form a 3-12-membered heterocyclic group, preferably a 3-6-membered heterocyclic group; the heterocyclic group is optionally further substituted by one or more substituents selected from halogen, amino, oxo, thio, nitro, cyano, hydroxyl, mercapto, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkylamino, alkenyl, alkynyl, C 3-6 cycloalkyl, 3-8-membered heterocyclic group, aryl, heteroaryl; Rd和Re各自独立地选自氢和C1-6烷基；R d and Re are each independently selected from hydrogen and C 1-6 alkyl; Rf选自C1-6烷基； Rf is selected from C 1-6 alkyl; p为1或2；p is 1 or 2; q为0至4的整数，优选0至2的整数；q is an integer from 0 to 4, preferably an integer from 0 to 2; R2、R3、R4、m如权利要求1所定义；Q2、n如权利要求3所定义。 R 2 , R 3 , R 4 and m are as defined in claim 1 ; Q 2 and n are as defined in claim 3 . 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，The compound represented by the general formula (I) according to any one of claims 1 to 3, or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein: Q1选自NRaRb；Q 1 is selected from NR a R b ; Ra选自氢和C1-6烷基；R a is selected from hydrogen and C 1-6 alkyl; Rb选自C1-6烷基，所述C1-6烷基任选进一步被选自-NRdRe、-NRdC(O)Rf、-C(O)NRdRe的取代基所取代；R b is selected from C 1-6 alkyl, wherein the C 1-6 alkyl is optionally further substituted by a substituent selected from -NR d R e , -NR d C(O)R f , -C(O)NR d R e ; Rd和Re各自独立地选自氢和C1-6烷基；R d and Re are each independently selected from hydrogen and C 1-6 alkyl; 或者Rd和Re与其相连的氮原子一起形成5-6元杂环基，所述5-6元杂环基任选进一步被选自卤素、氨基、氧代基、C1-6烷基的取代基所取代；or R d and Re together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally further substituted by a substituent selected from halogen, amino, oxo, C 1-6 alkyl; Rf选自C1-6烷基。 Rf is selected from C1-6 alkyl. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其为通式(IV)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，
The compound represented by the general formula (I) according to any one of claims 1 to 3, or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, which is a compound represented by the general formula (IV) or its stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt, wherein,
其中：in: X1、X2各自独立地选自CH或N；X 1 and X 2 are each independently selected from CH or N; Y3、Y4、Y5、Y6各自独立地选自CH或N，优选均为CH，或者其中之一为N，其余为CH，或者其中之二为N，其余为CH；Y 3 , Y 4 , Y 5 , and Y 6 are each independently selected from CH or N, preferably all are CH, or one of them is N and the others are CH, or two of them are N and the others are CH; 每个R13a各自独立地选自氢、卤素、C1-6烷基；s为0、1、2、3或4，优选0、1或2；Each R 13a is independently selected from hydrogen, halogen, C 1-6 alkyl; s is 0, 1, 2, 3 or 4, preferably 0, 1 or 2; R13b选自氢、卤素、氨基、氰基、C1-6烷基、C3-6环烷基、3-8元杂环基、-C(O)NRdRe、-C(O)NRf(CH2)qNRdRe；R 13b is selected from hydrogen, halogen, amino, cyano, C 1-6 alkyl, C 3-6 cycloalkyl, 3-8 membered heterocyclyl, -C(O)NR d R e , -C(O)NR f (CH 2 ) q NR d R e ; Rd和Re各自独立地选自氢、C1-6烷基、C3-6环烷基；R d and Re are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl; 或者Rd和Re与其相连的氮原子一起形成5-6元杂环基，所述5-6元杂环基任 选进一步被选自卤素、氨基、氧代基、C1-6烷基、5-6元杂环基的取代基所取代；Or R d and Re together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is Optionally, it is further substituted by a substituent selected from halogen, amino, oxo, C 1-6 alkyl, and 5-6 membered heterocyclic group; Rf选自氢和C1-6烷基； Rf is selected from hydrogen and C 1-6 alkyl; q为1至4的整数，优选1或2；q is an integer from 1 to 4, preferably 1 or 2; R2、R3、R4、m如权利要求1所定义；Q2、n如权利要求3所定义。R 2 , R 3 , R 4 and m are as defined in claim 1 ; Q 2 and n are as defined in claim 3 . 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，Q1选自8-10元稠杂环基，优选其任选进一步被选自C1-6烷基和C1-6卤代烷基的取代基所取代。The compound represented by the general formula (I) according to any one of claims 1 to 3, or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 is selected from an 8-10 membered fused heterocyclic group, preferably It is optionally further substituted with a substituent selected from C 1-6 alkyl and C 1-6 haloalkyl. 根据权利要求1所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，The compound represented by the general formula (I) according to claim 1 or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, 其中：in: R1为 R1 is L选自键、亚烷基或-C(O)-；L is selected from a bond, an alkylene group or -C(O)-; 环A选自C6-10芳基、5至10元杂芳基，优选苯基、萘基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吲哚基、吲唑基、喹啉基、喹喔啉基、喹唑啉基、吡啶并吡咯基、吡啶并咪唑基、苯并咪唑基、苯并吡唑基；其任选被一个或多个Q基团取代；Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, preferably phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl, quinolyl, quinoxalinyl, quinazolinyl, pyridopyrrolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl; which is optionally substituted by one or more Q groups; Q选自卤素、羟基、巯基、氰基、C1-6烷基、C1-6卤代烷基、-(CH2)qNRaRb；Q is selected from halogen, hydroxyl, mercapto, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -(CH 2 ) q NR a R b ; Ra和Rb各自独立地选自氢和C1-6烷基；R a and R b are each independently selected from hydrogen and C 1-6 alkyl; q为0-4的整数，优选0-2的整数。q is an integer of 0-4, preferably an integer of 0-2. 根据权利要求1至11中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，A compound represented by the general formula (I) according to any one of claims 1 to 11, or a stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, 其中，R2选自氢和C1-6烷基。Wherein, R2 is selected from hydrogen and C1-6 alkyl. 根据权利要求1所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R1和R2与其相连的氮原子一起形成5-10元杂环基或5-10元 杂芳基，优选8-10元杂环基，更优选其任选进一步被选自卤素、氨基、氰基、羟基、巯基、氧代基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、-(CH2)qNRaRb的一个或多个取代基所取代；The compound represented by the general formula (I) according to claim 1 or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 together with the nitrogen atom to which they are connected form a 5-10 membered heterocyclic group or a 5-10 membered Heteroaryl, preferably 8-10 membered heterocyclic group, more preferably which is optionally further substituted by one or more substituents selected from halogen, amino, cyano, hydroxyl, mercapto, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -(CH 2 ) q NR a R b ; q为1至4的整数，优选1或2；q is an integer from 1 to 4, preferably 1 or 2; Ra和Rb各自独立地选自氢或C1-6烷基。 Ra and Rb are each independently selected from hydrogen or C1-6 alkyl. 根据权利要求1至13中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，R3选自C1-6烷基或C1-6卤代烷基。A compound represented by the general formula (I) according to any one of claims 1 to 13, or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from C 1-6 alkyl or C 1-6 haloalkyl. 根据权利要求1至14中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，每个R4各自独立地选自氢、卤素、C1-6烷基、C1-6卤代烷基；m为0或1。A compound represented by the general formula (I) according to any one of claims 1 to 14, or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl; m is 0 or 1. 根据权利要求3至10中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其中，每个Q2各自独立地选自氢、卤素、C1-6烷基、C1-6烷氧基、氧代基、氰基、(CH2)qC(O)NRaRb、C1-6卤代烷基，所述C1-6烷基任选进一步被NRaRb取代；A compound represented by the general formula (I) according to any one of claims 3 to 10, or a stereoisomer, tautomer, mesoform, racemate, enantiomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein each Q 2 is independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, oxo, cyano, (CH 2 ) q C(O)NR a R b , C 1-6 haloalkyl, and the C 1-6 alkyl is optionally further substituted by NR a R b ; Ra和Rb各自独立地选自氢或C1-6烷基；R a and R b are each independently selected from hydrogen or C 1-6 alkyl; q为0至6的整数；q is an integer from 0 to 6; n为0至4的整数，优选0至2的整数。n is an integer of 0-4, preferably an integer of 0-2. 根据权利要求1-16中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，其选自：






The compound represented by the general formula (I) according to any one of claims 1 to 16, or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which is selected from:






一种制备通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的方法，其包括以下步骤：
A method for preparing a compound represented by general formula (I) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:
在碱性条件下，在缩合剂存在下，通式(IA)的化合物与通式(IB)的化合物发生缩合反应，得到通式(I)的化合物；Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IA) reacts with the compound of general formula (IB) to obtain a compound of general formula (I); 所述碱优选有机碱或无机碱，无机碱优选碳酸钾、碳酸铯、碳酸钠，有机碱优选DMAP、三乙胺、DIPEA；The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP, triethylamine, DIPEA; 所述缩合剂优选EDCI、DCC、CDI、HOBt、HOAT、HATU、TBTU、HBTU、PyBOP；The condensing agent is preferably EDCI, DCC, CDI, HOBt, HOAT, HATU, TBTU, HBTU, PyBOP; 其中：R1、R2、R3、R4、m如权利要求1所定义。wherein: R 1 , R 2 , R 3 , R 4 , and m are as defined in claim 1. 一种制备通式(IIIA)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐的方法，其包括以下步骤：
A method for preparing a compound represented by general formula (IIIA) or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:
在碱性条件下，在缩合剂存在下，通式(IIIAa)的化合物与通式(IIIAb)的化合物发生缩合反应，得到通式(IIIA)所示的化合物；Under alkaline conditions, in the presence of a condensing agent, the compound of general formula (IIIAa) undergoes a condensation reaction with the compound of general formula (IIIAb) to obtain a compound represented by general formula (IIIA); 所述碱优选有机碱或无机碱，无机碱优选碳酸钾、碳酸铯、碳酸钠，有机碱优选DMAP、三乙胺、DIPEA；The base is preferably an organic base or an inorganic base, the inorganic base is preferably potassium carbonate, cesium carbonate, sodium carbonate, and the organic base is preferably DMAP, triethylamine, DIPEA; 所述缩合剂优选EDCI、DCC、CDI、HOBt、HOAT、HATU、TBTU、HBTU、PyBOP；The condensing agent is preferably EDCI, DCC, CDI, HOBt, HOAT, HATU, TBTU, HBTU, PyBOP; 其中：R2、R3、R4、R7、R8、X1、X2、Y1、Q2、m、n如权利要求6所定义。wherein: R 2 , R 3 , R 4 , R 7 , R 8 , X 1 , X 2 , Y 1 , Q 2 , m and n are as defined in claim 6. 一种药物组合物，其包含根据权利要求1-17中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及一种或多种药学上可接受 的载体或赋形剂。A pharmaceutical composition comprising a compound represented by the general formula (I) according to any one of claims 1 to 17 or its stereoisomer, tautomer, mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carrier or excipient. 根据权利要求1-17中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求20所述的药物组合物在制备ATR激酶抑制剂中的用途。Use of a compound represented by the general formula (I) according to any one of claims 1 to 17 or its stereoisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20 in the preparation of an ATR kinase inhibitor. 根据权利要求1-17中任一项所述的通式(I)所示的化合物或其立体异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐或者根据权利要求20所述的药物组合物在制备用于治疗ATR激酶介导的疾病的药物中的用途，所述疾病优选黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌(包括小细胞肺癌、非小细胞肺癌和细支气管肺泡癌)、肾癌、膀胱癌、胆囊癌、乳腺癌、宫颈癌、卵巢癌、前列腺癌、皮肤癌、神经胶质瘤、肉瘤、骨癌、子宫癌、子宫内膜癌、甲状腺癌、头颈肿瘤、白血病(包括急性淋巴细胞白血病(ALL)、慢性髓细胞源性白血病(CML)以及急性髓细胞白血病(AML))、多发性骨髓瘤和淋巴癌。 Use of a compound represented by the general formula (I) according to any one of claims 1 to 17 or its stereoisomers, tautomers, mesoforms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 20 in the preparation of a medicament for treating an ATR kinase-mediated disease, wherein the disease is preferably melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer and bronchioalveolar carcinoma), kidney cancer, bladder cancer, gallbladder cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, glioma, sarcoma, bone cancer, uterine cancer, endometrial cancer, thyroid cancer, head and neck tumors, leukemia (including acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML)), multiple myeloma and lymphoma.
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